Pyridinone derivatives for treatment of atherosclerosis

ABSTRACT

Compounds of formula (I): are inhibitors of the enzyme L p -PLA 2  and are of use in therapy, in particular for treating atherosclerosis. 
 
Compounds of formula (I):  
                 
 
are inhibitors of the enzyme Lp-PLA 2  and are of use in therapy, in particular for treating atherosclerosis.

The present invention relates to certain novel pyrimidinone compounds,processes for their preparation, intermediates useful in theirpreparation, pharmaceutical compositions containing them and their usein therapy, in particular in the treatment of atherosclerosis.

WO 95/00649 (SmithKline Beecham plc) describes the phospholipase A₂enzyme Lipoprotein Associated Phospholipase A₂ (Lp-PLA₂), the sequence,isolation and purification thereof, isolated nucleic acids encoding theenzyme, and recombinant host cells transformed with DNA encoding theenzyme. Suggested therapeutic uses for inhibitors of the enzyme includedatherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardialinfarction, reperfusion injury and acute and chronic inflammation. Asubsequent publication from the same group further describes this enzyme(Tew D et al, Arterioscler Thromb Vas Biol 1996:16;591-9) wherein it isreferred to as LDL-PLA₂. A later patent application (WO 95/09921, IcosCorporation) and a related publication in Nature (Tjoelker et al, vol374, 6 Apr. 1995, 549) describe the enzyme PAF-AH which has essentiallythe same sequence as Lp-PLA₂ and suggest that it may have potential as atherapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA₂ is responsible for the conversion ofphosphatidylcholine to lysophosphatidylcholine, during the conversion oflow density lipoprotein (LDL) to its oxidised form. The enzyme is knownto hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to givelysophosphatidylcholine and an oxidatively modified fatty acid. Bothproducts of Lp-PLA₂ action are biologically active withlysophosphatidylcholine, in particular having several pro-atherogenicactivities ascribed to it including monocyte chemotaxis and induction ofendothelial dysfunction, both of which facilitate monocyte-derivedmacrophage accumulation within the artery wall. Inhibition of theLp-PLA₂ enzyme would therefore be expected to stop the build up of thesemacrophage enriched lesions (by inhibition of the formation oflysophosphatidylcholine and oxidised free fatty acids) and so be usefulin the treatment of atherosclerosis.

A recently published study (WOSCOPS—Packard et al, N. Engl. J. Med. 343(2000) 1148-1155) has shown that the level of the enzyme Lp-PLA₂ is anindependent risk factor in coronary artery disease.

The increased lysophosphatidylcholine content of oxidatively modifiedLDL is also thought to be responsible for the endothelial dysfunctionobserved in patients with atherosclerosis. Inhibitors of Lp-PLA₂ couldtherefore prove beneficial in the treatment of this phenomenon. AnLp-PLA₂ inhibitor could also find utility in other disease states thatexhibit endothelial dysfunction including diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

In addition, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves activated monocytes, macrophages orlymphocytes, as all of these cell types express Lp-PLA₂. Examples ofsuch disorders include psoriasis.

Furthermore, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves lipid oxidation in conjunction with Lp-PLA₂activity to produce the two injurious products, lysophosphatidylcholineand oxidatively modified fatty acids. Such conditions include theaforementioned conditions atherosclerosis, diabetes, rheumatoidarthritis, stroke, myocardial infarction, ischaemia, reperfusion injuryand acute and chronic inflammation.

Patent applications WO 96/12963, WO 96/13484, WO 96/19451, WO 97/02242,WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKlineBeecham plc) disclose inter alia various series of4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitorsof the enzyme Lp-PLA₂. These are irreversible, acylating inhibitors (Tewet al, Biochemistry, 37, 10087, 1998).

A further class of compounds has now been identified which arenon-acylating inhibitors of the enzyme Lp-PLA₂. Thus, WO 99/24420, WO00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline Beechamplc) disclose a class of pyrimidone compounds. We have now found thatthe pyrimidone ring may be replaced by a pyridone ring, to givecompounds having good activity as inhibitors of the enzyme Lp-PLA₂.

Accordingly, the present invention provides a compound of formula (I):

in which:

-   -   R¹ is an aryl group, optionally substituted by 1, 2, 3 or 4        substituents which may be the same or different selected from        C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, hydroxy, halogen,        CN, mono to perfluoro-C(₁₋₄₎alkyl, mono to        perfluoro-C₍₁₋₄₎alkoxyaryl, and arylC₍₁₋₄₎alkyl;    -   R² is halogen, C₍₁₋₃₎alkyl, C₍₁₋₃₎alkoxy, hydroxyC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylthio, C₍₁₋₃₎alkylsulphinyl, aminoC₍₁₋₃₎alkyl, mono-        or di-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylcarboxy,        C₍₁₋₃₎alkylcarboxyC₍₁₋₃₎alkyl, and    -   R³ is hydrogen, halogen, C₍₁₋₃₎alkyl, or hydroxyC₍₁₋₃₎alkyl; or    -   R² and R³ together with the pyridone ring carbon atoms to which        they are attached form a fused 5-or 6-membered carbocyclic ring;        or    -   R² and R³ together with the pyridone ring carbon atoms to which        they are attached form a fused benzo or heteroaryl ring        optionally substituted by 1, 2, 3 or 4 substituents which may be        the same or different selected from halogen, C₍₁₋₄₎alkyl, cyano,        C₍₁₋₃₎alkoxyC₍₁₋₃₎alkyl, C₍₁₋₄₎alkoxy or C₍₁₋₄₎alkylthio, or        mono to perfluoro-C₍₁₋₄₎alkyl;    -   R⁴ is hydrogen, C₍₁₋₆₎alkyl which may be unsubstituted or        substituted by 1, 2 or 3 substituents selected from hydroxy,        halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹R¹⁰, NR⁷COR⁸,        mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino and        N-hydroxyC₍₁₋₆₎alkyl-N—C₍₁₋₆₎alkylamino; or    -   R⁴ is Het-C₍₀₋₄₎alkyl in which Het is a 5- to 7- membered        heterocyclyl ring comprising N and optionally O or S, and in        which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or        C₍₁₋₆₎alkyl optionally substituted by 1, 2 or 3 substituents        selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷,        CONR⁹R¹⁰ or NR⁹R¹⁰, for instance, piperidin-4-yl,        pyrrolidin-3-yl;    -   R⁵ is an aryl or a heteroaryl ring optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio,        arylC₍₁₋₆₎alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷,        NR⁷COR⁸, CONR⁹R¹⁰, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;    -   R⁶ is an aryl or a heteroaryl ring which is further optionally        substituted by 1, 2, 3 or 4 substituents which may be the same        or different selected from C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy,        C₍₁₋₆₎alkylthio, C₍₁₋₆₎alkylsulfonyl, arylC₍₁₋₆₎alkoxy, hydroxy,        halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, SO₂NR⁹R¹⁰        , NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alkyl and mono to        perfluoro-C₍₁₋₄₎alkoxy, or C₍₅₋₁₀₎alkyl;    -   R⁷ and R⁸ are independently hydrogen or C₍₁₋₁₂₎alkyl, for        instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl);    -   R⁹ and R¹⁰ which may be the same or different is each selected        from hydrogen, or C₍₁₋₁₂₎alkyl, or R⁹ and R¹⁰ together with the        nitrogen to which they are attached form a 5- to 7 membered ring        optionally containing one or more further heteroatoms selected        from oxygen, nitrogen and sulphur, and optionally substituted by        one or two substituents selected from hydroxy, oxo, C₍₁₋₄₎alkyl,        C₍₁₋₄₎alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl,        for instance morpholine or piperazine; and    -   X is a C₍₂₋₄₎alkylene group (optionally substituted by 1, 2 or 3        substituents selected from methyl and ethyl), CH═CH, (CH₂)_(n)S        or (CH₂)_(n)O where n is 1, 2 or 3.

In a further aspect the present invention provides a compound of formula(I) as defined above in which:

-   -   R² and R³ together with the pyridone ring carbon atoms to which        they are attached form a fused benzo or heteroaryl ring        optionally substituted by 1, 2, 3 or 4 substituents which may be        the same or different selected from halogen, C₍₁₋₄₎alkyl, cyano,        C₍₁₋₄₎alkoxy or C(₁ ₄)alkylthio, or mono to        perfluoro-C₍₁₋₄₎alkyl.

Representative examples of R¹ when an aryl group include phenyl andnaphthyl. Preferably, R¹ is phenyl optionally substituted by halogen,C₍₁₋₆₎alkyl, trifluoromethyl, C₍₁₋₆₎alkoxy, preferably, from 1 to 3fluoro, more preferably, 2,3-difluoro.

Representative examples of R² include methyl, ethyl, and trifluoroethylwhen R³ is hydrogen.

Representative examples of R³ include methyl when R² is methyl.

Further representative examples of R² and R³ include when R² and R³together with the pyridone ring carbon atoms to which they are attachedform a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fusedbenzo, pyrido, pyrazolo or thieno ring.

Further representative examples of R² and R³ include when R² and R³,together with the pyridone ring carbon atoms to which they are attached,form a pyrazolo ring substituted on the N atom by C₍₁₋₃₎alkyl ormethoxyethyl; and when R² and R³, together with the pyridone ring carbonatoms to which they are attached, form either a thiazolyl, thieno orpyrido ring substituted by methyl.

Preferably, R² and R³ together with the pyridone ring carbon atoms towhich they are attached form a fused 5-membered carbocyclic(cyclopentenyl) ring or a fused benzo, pyrido, thieno or pyrazolo ring.

Preferably, R² and R³, together with the pyridone ring carbon atoms towhich they are attached, form a fused thiazolyl ring substituted bymethyl.

Representative examples of R⁴ include hydrogen, methyl,2-diethylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl,3-(morpholin-4-yl)propyl, 1-ethyl-piperidin-4-yl and1-ethyl-pyrrolidin-2-ylmethyl. Preferably R⁴ is 2-(diethylamino)ethyl or1-ethyl-piperidin-4-yl.

Further representative examples of R⁴ include piperidin-4-yl substitutedat the 1-position by methyl, isopropyl, 1-(2-methoxyethyl),1-(2-hydroxyethyl), t-butoxycarbonyl or ethoxycarbonylmethyl; ethylsubstituted at the 2-position by aminoethyl; 1-ethylpiperidinylmethyl;piperidin-4-yl; 3-diethylaminopropyl; 4-pyrrolidin-1-ylbutyl and1-ethylpyrrolidin-3-yl.

Preferably R⁴ is 1-(2-methoxyethyl)piperidin-4-yl,1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl.

Representative examples of R⁵ include phenyl and pyridyl. Preferably, R⁵is phenyl.

Representative examples of R⁶ include phenyl optionally substituted byhalogen, or trifluoromethyl, preferably at the 4-position and hexyl.Preferably, R⁶ is phenyl substituted by trifluoromethyl at the4-position.

Further representative examples of R⁶ include phenyl substituted by 1 ormore C₍₁₋₃₎alkyl. Preferably, R⁶ is phenyl substituted by ethyl in the4-position.

Preferably, R⁵ and R⁶ together form a 4-(phenyl)phenyl or a2-(phenyl)pyridinyl substituent in which the remote phenyl ring may beoptionally substituted by halogen or trifluoromethyl, preferably at the4-position.

Preferably X is C₍₂₋₄₎alkylene, more preferably C₍₂₋₃₎alkylene, mostpreferably, (CH₂)₂, or CH₂S.

It will be appreciated that within the compounds of formula (I) there isa sub-group of compounds (group A) in which:

-   -   R¹ is phenyl substituted by 2,3-difluoro;    -   R² and R³, together with the pyridone ring carbon atoms to which        they are attached, form a fused 5-membered carbocyclic        (cyclopentenyl) ring, or a fused benzo or pyrido ring;    -   R⁴ is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,        1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or        1-ethylpyrrolidin-3-yl;    -   R⁵ is phenyl;    -   R⁶ is phenyl substituted by ethyl or trifluoromethyl in the        4position; and    -   X is CH₂S.

It will be appreciated that within the compounds of formula (I) there isa further sub-group of compounds (group B) in which:

-   -   R¹ is phenyl substituted by 2,3-difluoro;    -   R² and R³, together with the pyridone ring carbon atoms to which        they are attached, form a fused thiazolyl ring substituted by        methyl, or a benzo or pyrido ring;    -   R⁴ is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,        1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or        1-ethylpyrrolidin-3-yl;    -   R⁵ is phenyl;    -   R⁶ is phenyl substituted by trifluoromethyl in the 4-position;        and    -   X is (CH₂)₂.

It will be appreciated that within the compounds of formula (I) there isa further sub-group of compounds (group C) in which:

-   -   R¹ is phenyl substituted by 2,3-difluoro;    -   R² and R³, together with the pyridone ring carbon atoms to which        they are attached, form a fused benzo or pyrido ring;    -   R⁴ is 1-(2-methoxyethyl)piperidin-4-yl;    -   R⁵ and R⁶ together form a 4-(phenyl)phenyl substituent in which        the remote phenyl ring is substituted by trifluoromethyl,        preferably at the 4-position; and    -   X is CH₂S or (CH₂)₂.

It will be appreciated that compounds of the present invention maycomprise one or more chiral centres so that stereoisomers may be formed.The present invention covers all such stereoisomers, includingindividual diastereoisomers and enantiomers, and mixtures thereof.

It will be appreciated that in some instances, compounds of the presentinvention may include a basic function such as an amino group as asubstituent. Such basic functions may be used to form acid additionsalts, in particular pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts include those described by Berge, Bighley, andMonkhouse, J. Pharm. Sci, 1977, 66, 1-19. Such salts may be formed frominorganic and organic acids. Representative examples thereof includemaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic,palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholicacid, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic,sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that in some instances, compounds of the presentinvention may include a carboxy group as a substituent. Such carboxygroups may be used to form salts, in particular pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts include thosedescribed by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66,1-19. Preferred salts include alkali metal salts such as the sodium andpotassium salts.

When used herein, the term “alkyl” and similar terms such as “alkoxy”includes all straight chain and branched isomers. Representativeexamples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

When used herein, the term “aryl” refers to, unless otherwise defined, amono- or bicyclic aromatic ring system containing up to 10 carbon atomsin the ring system, for instance phenyl or naphthyl.

When used herein, the term “heteroaryl” refers to a mono- or bicyclicheteroaromatic ring system comprising up to four, preferably 1 or 2,heteroatoms each selected from oxygen, nitrogen and sulphur. Each ringmay have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclicheteroaromatic ring system may include a carbocyclic ring.

When used herein, the terms “halogen” and “halo” include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo and iodo,respectively.

Most preferred compounds of formula (I) are:

-   -   N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;    -   N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;    -   or a pharmaceutically acceptable salt thereof, in particular the        bitartrate, hydrochloride, dihydrochloride or        paratoluenesulfonate salt.

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compounds of formula (I) may be used for preparingthe more pure forms used in the pharmaceutical compositions. Althoughthe purity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are obtained incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are re-crystallised from organic solvents, solvent of crystallisationmay be present in the crystalline product This invention includes Withinits scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or re-crystallised from solventscontaining water. In such cases water of hydration may be formed. Thisinvention includes within its scope stoichiometric hydrates as well ascompounds containing variable amounts of water that may be produced byprocesses such as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope allpolymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzymelipoprotein associated phospholipase A₂ (Lp-PLA₂) and as such areexpected to be of use in therapy, in particular in the treatment ofatherosclerosis. In a further aspect therefore the present inventionprovides a compound of formula (I) for use in therapy.

The compounds of formula (I) are inhibitors of lysophosphatidylcholineproduction by Lp-PLA₂ and may therefore also have a general applicationin any disorder that involves endothelial dysfunction, for exampleatherosclerosis, diabetes, hypertension, angina pectoris and afterischaemia and reperfusion. In addition, compounds of formula (I) mayhave a general application in any disorder that involves lipid oxidationin conjunction with enzyme activity, for example in addition toconditions such as atherosclerosis and diabetes, other conditions suchas rheumatoid arthritis, stroke, inflammatory conditions of the brainsuch as Alzheimer's Disease, myocardial infarction, ischaemia,reperfusion injury, sepsis, and acute and chronic inflammation.

Further applications include any disorder that involves activatedmonocytes, macrophages or lymphocytes, as all of these cell typesexpress Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for amethod of treating a disease state associated with activity of theenzyme Lp-PLA₂ which method involves treating a patient in need thereofwith a therapeutically effective amount of an inhibitor of the enzyme.The disease state may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidised free fatty acids; with lipidoxidation in conjunction with Lp-PLA₂ activity; or with endothelialdysfunction.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLp(a). Examples of the above include cholesterol synthesis inhibitorssuch as statins, anti-oxidants such as probucol, insulin sensitisers,calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.Examples of agents for lowering Lp(a) include the aminophosphonatesdescribed in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312(Symphar SA and SmithKline Beecham).

A preferred combination therapy will be the use of a compound of thepresent invention and a statin. The statins are a well known class ofcholesterol lowering agents and include atorvastatin, simvarstatin,pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin(also referred to as S-4522 or ZD 4522, Astra Zeneca). The two agentsmay be administered at substantially the same time or at differenttimes, according to the discretion of the physician.

A further preferred combination therapy will be the use of a compound ofthe present invention and an anti-diabetic agent or an insulinsensitiser, as coronary heart disease is a major cause of death fordiabetics. Within this class, preferred compounds for use with acompound of the present invention include the PPARgamma activators, forinstance G1262570 (GlaxoSmithKline) and the glitazone class of compoundssuch as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone andpioglitazone.

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository. Compounds offormula (I) which are active when given orally can be formulated asliquids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges. A liquid formulation will generally consist of asuspension or solution of the compound or pharmaceutically acceptablesalt in a suitable liquid carrier(s) for example, ethanol, glycerine,non-aqueous solvent, for example polyethylene glycol, oils, or waterwith a suspending agent, preservative, flavouring or colouring agent. Acomposition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier(s), for example aqueous gums,celluloses, silicates or oils and the dispersion or suspension thenfilled into a soft gelatin capsule. Typical parenteral compositionsconsist of a solution or suspension of the compound of formula (I) in asterile aqueous carrier or parenterally acceptable oil, for examplepolyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil orsesame oil. Alternatively, the solution can be lyophilised and thenreconstituted with a suitable solvent just prior to administration. Atypical suppository formulation comprises a compound of formula (I)which is active when administered in this way, with a binding and/orlubricating agent such as polymeric glycols, gelatins or cocoa butter orother low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule. Each dosage unit for oral administration contains preferablyfrom 1 to 500 mg (and for parenteral administration contains preferablyfrom 0.1 to 25 mg) of a compound of the formula (I). The daily dosageregimen for an adult patient may be, for example, an oral dose ofbetween 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or anintravenous, subcutaneous, or intramuscular dose of between 0.1 mg and100 mg, preferably between 0.1 mg and 25 mg, of the compound of theformula (I), the compound being administered 1 to 4 times per day.Suitably the compounds will be administered for a period of continuoustherapy, for example for a week or more.

A compound of formula (I) may be prepared by reacting an acid compoundof formula (II):

in which X, R¹ , R² and R³ are as hereinbefore defined, with an aminecompound of formula (III):R⁶—R⁵—CH₂NHR⁴   (III)in which R⁴, R⁵ and R⁶ are as hereinbefore defined; under amide formingconditions.

Suitable amide forming conditions are well known in the art and includetreating the acid of formula (II) with the amine of formula (III) in thepresence of a coupling agent such as1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (DEC) and1-hydroxybenzotriazole (HOBt), orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and di-isopropylethylamine, in an aproticsolvent such as dichloromethane or dimethylformamide.

A compound of formula (II) may be readily prepared from a correspondingester of formula (IV):

in which X, R¹, R² and R³ are as hereinbefore defined, and R¹¹ isC₍₁₋₆₎alkyl, for example ethyl or t-butyl,

-   -   by treating with a de-esterifying agent, for instance, when R¹¹        is t-butyl, trifluoroacetic acid or when R¹¹ is ethyl, sodium        hydroxide in dioxan.

The overall synthesis of compounds of formula (I) is illustrated in thefollowing scheme wherein R¹ to R¹¹ are as hereinbefore defined:

Referring to the scheme, the ester (IV) is usually prepared by N-1alkylation of (V) using (VI), in which R¹¹ is as hereinbefore definede.g. (VI) is t-butyl bromoacetate or ethyl bromoacetate, in the presenceof a base e.g. BuLi in THF or sodium hydride in N-methyl pyrrolidinone(NMP) (step c).

When X is CH₂S, the key intermediate (IV) may be synthesised by reacting(XX) with dimethyloxosulfonium methylide, generated via the treatment oftrimethylsulfoxonium iodide with sodium hydride at-low temperature, toyield a sulfur ylid (XXII) (step q). Subsequent treatment of (XXII) withcarbon disulfide in the presence of diisopropylamine, followed by R¹CH₂-L⁴, where L⁴ is a leaving group, yields intermediate (IV) (step r).

Alternatively, when X is CH₂S, the R¹X substituent may be introduced bydisplacement of a leaving group L² (e.g. Cl) (step e) either on apyridine (VIII) or pyridine N-oxide (XIV), to give 2-substitutedpyridines (VII) and (XV). Transformation of (VII) or (XV) to the4-pyridone (V) is accomplished by deprotection of the 4-oxygen (e.g.using (Ph₃P)₃RhCl when in aq. ethanol when R¹²=allyl) (step d),followed, for (XVI), by removal of the N-oxide substituent, usinghydrogen in the presence of Pd/C in acetic acid (step k). The pyridine(VIII) or pyridine N-oxide (XIV) may be prepared by steps (i), (h), (g),(f), and G), in which:

-   -   (j) treatment of (VIII) with m-chloroperbenzoic acid in        dichloromethane;    -   (f) treatment of (IX) with R¹²OH (X), in which R¹² is allyl, and        sodium hydride in DMF;    -   (g) treatment of (XI) with phosphorus oxychloride;    -   (h) treatment of (XII) with aq HCl with heating;    -   (i) treatment of (XIII) with di-lower alkyl malonate and sodium        alkoxide in alcohol (in which R¹³ is C₍₁₋₆₎alkyl, typically        R¹³=Et); and    -   R¹ CH₂SH (XIX) is typically prepared from the thioacetate, which        is formed from the corresponding alkyl bromide R¹—CH₂Br.

Alternatively, when X is CH₂S and R² and R³, together with the pyridonering carbon atoms to which they are attached, form a fused benzo ring,intermediate (IV) may be synthesised from known starting materials bysteps (s), (c) and (v) in which:

-   -   (s) treatment of Meldrum's acid (XXIII) with sodium hydride at        low temperature, followed by reaction with phenylisothiocyanate        and subsequent treatment with R¹CH₂-L⁴;    -   (c) as hereinbefore discussed;    -   (v) treatment of (XXV) with trifluoroacetic acid.

When X is alkylene, it is preferable to use steps (m) and (h)(intermediates (XVII), (XVIII)) or steps (n) and (p) (intermediates(XIX), (XX), (XXI)) in which:

-   -   (h) transformation of a 4-substituted pyridine into a 4-pyridone        e.g. by treatment of (XVII) R¹⁴═Cl with aq HCl and dioxan, or        deprotection of R¹⁴═OR¹², e.g. using conditions of step (d).    -   (m) chain extension of a 2-alkyl pyridine, e.g. where X═YCH₂CH₂        by treatment of a 2-methylpyridine (XVIII) with        R¹—Y—CH₂-L⁴ (XVI) in which L⁴ is a leaving group and a strong        base, such as BuLi, in THF.

In the alternative route, the 3-ester group is removed from intermediate(XIX) R¹⁵═C₍₁₋₆₎alkyl by heating in diphenyl ether where R¹⁵=tBu (stepn); Intermediate (XIX) is formed from the 2,6-dioxo-1,3-oxazine (XX) andester (XXI) by treatment with a base such as NaH in DMF or1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane.

Synthesis of (XX) from known starting materials may be achieved viasteps (w) and (c) or steps (y) and (c) in which:

-   -   (w) treatment of(VII) with azidotrimethylsilane in THF;    -   (y) treatment of (XXVI) with phosgene;    -   (c) as hereinbefore described.

It will be appreciated by those skilled in the art that all otherstarting materials and intermediates are either known compounds or maybe prepared by literature methods, such as those described in“Comprehensive Organic Transformations: a guide to functional grouppreparations” by Richard Larock (VCH, 1989), incorporated herein byreference.

As will be appreciated by those skilled in the art it may be necessaryor desirable at any stage in the synthesis of compounds of formula (I)to protect one or more sensitive groups in the molecule so as to preventundesirable side reactions. The protecting groups used in thepreparation of compounds of formula (I) may be used in conventionalmanner. See for example, those described in ‘Protective Groups inOrganic Synthesis’ by Theodora W Green and Peter G M Wuts, secondedition, (John Wiley and Sons, 1991), incorporated herein by reference,which also describes methods for the removal of such groups.

The present invention will now be illustrated by the following examples.

EXAMPLES

The structure and purity of the intermediates and examples was confirmedby 1H-NMR and (in nearly all cases) mass spectroscopy, even where notexplicitly indicated below

Intermediate A1 4-(4-Trifluoromethylphenyl)benzaldehyde

A 3 L 3-neck flask fitted with top stirrer, condenser and argoninlet/outlet was charged with 4-trifluoromethybenzene boronic acid (90.0g, 0.474 mol), 4-bromobenzaldehyde (83.29 g, 0.450 mol) and1,2-dimethoxyethane (1.3 L), followed by 2M aqueous sodium carbonate(474 ml) and palladium acetate (5.32 g, 0.0237 mol). The stirringmixture was heated to reflux for 4 h under argon, then allowed to coolto room temperature over 16 h. The reaction mixture was filtered throughhyflo. The filtrate was diluted with saturated brine and extracted 3×with ethyl acetate. The combined extracts were dried over magnesiumsulfate and filtered through hyflo, giving a clear orange filtrate whichwas evaporated to a solid (ca. 120 g, crude). Flash chromatography(silica, 10-50% dichloromethane in pet. ether, 10% steps) gave a whitesolid which dissolved in hexane (500 ml) on boiling. Crystallisation,finally in ice, gave the title compound as a solid which was filteredoff, washed with ice cold hexane and dried, (86.33 g, 77%). ¹H-NMR(CDCl₃) δ 7.77-8.03 (8H, m), 10.09 (1H, s).

Intermediate A2N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine

4-(4-Trifluoromethylphenyl)benzaldehyde (85.43 g, 0.3414 mol) (Int. A1)and 4 A molecular sieve (400 g, predried at 120° C.) were suspended indichloromethane (1.4 L), then N,N-diethyl-ethylenediamine (47.97ml,0.3414 mol) was added. The mixture was left at room temperature for 16 hwith occasional shaking, then the sieves were filtered off and washedwith dichloromethane. The combined filtrates were evaporated to a yellowsolid and dried under high vacuum. This material (114.3 g, 0.328 mol) inethanol (1 L) was cooled in an ice bath, and sodium borohydride (12.41g, 0.328 mol) was added under argon with stirring. Hydrogen evolutionwas observed. After 30 min the ice bath was removed, and the cloudyyellow solution was left to stand at room temperature for 16 h. Thesolvent was removed in vacuo, water and brine were added, and themixture was extracted 3× with dichloromethane. The combined extractswere dried over potassium carbonate and evaporated to give the titlecompound as a yellow solid, (112.1 g, 98%). ¹H-NMR (CDCl₃) δ 7.66 (4H,s), 7.53-7.56 (2H, m), 7.40-7.44 (2H, m), 3.86 (2H, s), 2.47-2.75 (9H,m), 0.96-1.10 (6H, m); MS(APCI+) found (M+1)=-351, C₂₀H₂₅F₃N₂ requires350.

Intermediate A3—4-(4-Trifluoromethylphenyl)benzonitrile

Prepared by the method of intermediate A1 using4-trifluoromethylbenzeneboronic acid and 4-bromobenzonitrile. ¹H-NMR (d6DMSO) δ 7.99-7.94 (6H, m), 7.86 (2H, d); MS(APCI+) found (M+1)=248,C₁₄H₈NF₃ requires 247.

Intermediate A4—4-(4-Trifluoromethylphenyl)benzylamine, Free Base andhydrochloride salt

(a) A solution of intermediate A3 (75.5 g, 0.306 mol) in anhydrous THF(500 ml) was added dropwise to a solution of lithium aluminum hydride(460 ml, 1.0M solution in THF) at 0° C. under argon. The mixture wasstirred at room temperature for 16 h, then water (17 ml), 10% aqueoussodium hydroxide solution (10 ml) and water (50 ml) were carefully addeddropwise over 8 h under argon. The mixture was stirred for 16 h, thenfiltered through celite and the filtrate evaporated. The residue wasdissolved in dichloromethane (500 ml) and washed with brine, dried andevaporated to give the title compound as a cream solid (66.3 g, 86%).¹H-NMR (CDCl₃) δ 7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d), 3.94 (2H, s),1.50 (2H, s); MS(APCI+) found (M-NH₂)=235, C₁₄H₁₂F₃N requires 251.

(b) To a solution of intermediate A3 (96.7 g, 0.39 mol) in absoluteethanol (5 L) and concentrated hydrochloric acid (200 ml) was added 10%palladium on charcoal (30.0 g, 54% H₂O paste). The mixture was stirredunder 50 psi hydrogen for 16 h. Additional 10% palladium on charcoal(25.0 g, 54% H₂O paste) was added and the mixture was stirred under 50psi hydrogen for &firther 16 h. The mixture was filtered through celiteand the solvent evaporated to give the hydrochloride salt of the titlecompound as a cream solid (102.5 g, 91%). ¹H-NMR (d6 DMSO) δ 8.61 (3H,s), 7.93 (2H, d), 7.83 (2H, d), 7.80 (2H, d), 7.65 (2H, d), 4.08 (2H,s); MS(APCI+) found (M-NH₂)=235, C₁₄H₁₂F₃N requires 251.

IntermediateA5—N-(1-Methyl-piperidin-4-yl)-4-(4-trifluoromethylphenyl)benzylamine

A mixture of intermediate A4 hydrochloride salt (6.0 g, 20.87 mnmol),1-methyl-piperidin-4-one (2.56 ml, 20.84 mmol), sodiumtriacetoxyborohydride (6.20 g, 29.25 mmol) and acetic acid (1.3 ml) indichloroethane (50 ml) was stirred at room temperature under argon for16 h then poured into 2M sodium hydroxide solution (150 ml). The organicphase was separated and the aqueous layer extracted withdichloromethane. The combined organic phases were washed with brine,dried and evaporated. Chromatography (silica, dichloromethane to 97:3dichloromethane/methanolic ammonia) gave the product as a cream solid(6.3 g, 87%). ¹H-NMR (CDCl₃) δ 7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d),3.87 (2H, s), 2.82 (2H, m), 2.52 (1H, m), 2.27 (3H, s), 1.90-2.02 (4H,m), 1.45-1.51 (2H, m); MS(APCI+) found (M+1)=349, C₂₀H₂₃N₂F₃ requires348.

The following intermediate was made as described in WO 00/66567 No.Structure Name A6

4-(4- Chlorophenyl)- benzylamine

The following intermediates were made by the method of Intermediate A1:No. Precursors Name A7 4-bromobenzaldehyde,4-(4-methylphenyl)benzaldehyde 4-methylbenzeneboronic acid A84-bromobenzaldehyde, 4-(4-ethylphenyl)benzaldehyde 4-ethylbenzeneboronicacid A9 4-isopropyliodobenzene 4-(4-isopropylphenyl)benzaldehyde4-formylbenzeneboronic acid A10 4-bromo-o-xylene 4-(3,4-dimethylphenyl)4-formylbenzeneboronic acid benzaldehyde A11 3,4-difluoroiodobenzene4-(3,4-difluorophenyl) 4-formylbenzeneboronic acid benzaldehyde

The following intermediates were made by the method of Intermediate A2:Amine precursors were either commercially available, or readily preparedfrom commercially available materials by literature methods or minormodifications thereof. No. Precursor Structure Name A20 Int. A1

N-(2-piperidin-1-yl)ethyl)-4-(4- trifluoromethylphenyl)benzylamine A22Int. A1

N-(2-(pyrrolidin-1-yl)ethyl)-4-(4- trifluoromethylphenyl)benzylamine A23Int. A1

(±)-N-(1-ethylpyrrolidin-2-ylmethyl)- 4-(4-trifluoromethyl-phenyl)benzylamine A24 Int. A1

N-(3-diethylaminopropyl)-4-(4- trifluoromethylphenyl)benzylamine A25Int. A1

N-(1-ethylpiperidin-4-ylmethyl)-4-(4- trifluoromethylphenyl)benzylamineA26 Int. A7

N-(2-diethylaminoethyl)-4-(4-methyl- phenyl)benzylamine A27 Int. A8

N-(2-diethylaminoethyl)-4-(4-ethyl- phenyl)benzylaniine A28 Int. A9

N-(2-diethylaminoethyl)-4-(4- isopropylphenyl)benzylamine A29 Int. A8

N-(1-ethylpiperidin-4-yl)-4-(4-ethyl- phenyl)benzylamine A30 Int. A10

N-(2-diethylaminoethyl)-4-(3,4- dimethylphenyl)benzylamine A31 Int. A11

N-(2-diethylaminoethyl)-4-(3,4- difluorophenyl)benzylamine A32 Int. A1

N-(4-(pyrrolidin-1-yl)butyl)-4-(4- trifluoromethylphenyl)benzylamine A33Int. A1

N-(2-(N′-t-butoxycarbonyl-N′- ethylamino)ethyl)-4-(4-trifluoro-methylphenyl)benzylamine

The following intermediates were made by the method of Intermediate A5:Piperidone precursors were either commercially available, or readilyprepared from commercially available materials by literature methods orminor modifications thereof. No. Precursor Structure Name A40 Int. A4

N-(1-ethylpiperidin-4-yl)-4-(4- trifluoromethyl phenyl)benzylamine A41Int. A4

N-(1-isopropylpiperidin-4-yl)-4- (4-trifluoromethyl- phenyl)benzylamineA42 Int. A4

N-(1-(2-methoxyethyl)piperidin-4- yl)-4-(4-trifluoromethylphenyl)-benzylamine A43 Int. A4

N-(1- ethoxycarbonylmethylpiperidin-4- yl)-4-(4-trifluoromethylphenyl)-benzylamine A44 Int. A6

N-(1-ethylpiperidin-4-yl)-4- (chlorophenyl)benzylamine A45 Int. A6

N-(1-methylpiperidin-4-yl)-4-(4- chlorophenyl)benzylamine A46 Int. A6

N-(1-isopropylpiperidin-4-yl)-4- (4-chlorophenyl)benzylamine A47 Int. A6

N-(1-(2-methoxyethyl)piperidin-4- yl)-4-(4-chlorophenyl)- benzylamineA48 Int. A4

N-(1-(t-butoxycarbonyl)piperidin- 4-yl)-4-(4-trifluoromethyl-phenyl)benzylamine

Intermediate B1—Thioacetic acid S-(2,3-difluorobenzyl)ester

Potassium thioacetate (13.45 g, 1.2 equiv) was added portionwise to asolution of 2,3-difluorobenzyl bromide (20 g, 1 equiv) indimethylformamide (200 ml) and the reaction stirred for 4 h at roomtemperature. The resultant solid was filtered off and the filtratepartitioned between diethyl ether and water, the organic phase was driedand evaporated. Chromatography (silica, 20:1 petrol/ethyl acetate) gavethe title compound as a yellow oil (18.35 g). ¹H-NMR (CDCl₃) δ 2.35 (3H,s), 4.15 (2H, d), 6.98-7.13 (3H, m).

Intermediate B2—2,3-Difluorobenzyl mercaptan

A mixture of thioacetic acid S-(2,3-difluorobenzyl)ester (IntermediateB 1) (18.35 g, 1 equiv) and potassium carbonate (25.11 g, 2 equiv) inmethanol (200 ml) and water (400 ml) was stirred overnight before beingpoured into dichloromethane (500 ml). The organic phase was dried andevaporated and distilled (125° C.@5.6 mBar) to give the title compoundas a colourless oil (12.15 g). ¹H-NMR (CDCl₃) δ 1.89 (1H, t), 3.78 (2H,d), 7.05 (3H, m).

Intermediate B3—Ethyl2,4-dihydroxy-6,7-dihydro-5H-[1]pyrindine-3-carboxylate

A mixture of ethyl 2-amino-1-cyclopentene-1-carboxylate (10.1 g, 1equiv), diethyl malonate (9.9 ml, 1 equiv), sodium ethoxide (26.7 ml,1.1 equiv, 21 wt % solution in ethanol) in ethanol was heated in asealed vessel to 110° C. for 96 h. After cooling the solvent was removedand the residue suspended in water. The suspension was acidified withaqueous hydrochloric acid (pH˜3) and the precipitate was collected anddried to give the title compound as a light brown solid (11.52 g).¹H-NMR (d6-DMSO) δ 1.27 (3H, t), 2.00 (2H, qn), 2.60 (2H, t), 2.73 (2H,t), 4.30 (2H, q), 11.62 (1H, br s), 13.18 (1H, br s).

Intermediate B4—2,4-Dihydroxy-6,7-dihydro-5H-[1]pyrindine

A mixture of ethyl2,4-dihydroxy-6,7-dihydro-5H-[1]pyrindine-3-carboxylate (Int. B3) (11.52g) and aqueous hydrochloric acid (2M, 100 ml) was heated togetherovernight. After cooling the solvent was removed by freeze drying andthe title compound obtained as a brown solid (8.02 g). ¹H-NMR (d₆-DMSO)2.09 (2H, qn), 2.72 (2H, t), 2.93 (2H, t), 6.56 (1H, s); MS (APCI+)found (M+1)=152; C₈H₉NO₂ requires 151.

Intermediate B5—2,4-Dichloro-6,7-dihydro-5H-[1]pyrindine

A mixture of 2,4dihydroxy-6,7-dihydro-5H-[1]pyrindine (Int. B4) (8.02 g)and phosphorous oxychloride (40 ml) was heated to reflux overnight. Theexcess phosphorous oxychloride was evaporated off and the residue pouredover ice. The resulting brown solid was filtered off and dried (7.36 g).¹H-NMR (CDCl₃) δ 2.17 (2H, m), 2.96 (2H, t), 3.07 (2H, t), 7.12 (1H, s);MS (APCI+) found (M+1)=188; C₈H₇ ³⁵Cl₂N requires 187.

Intermediate B6—4-Allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine

Allyl alcohol (4.1 ml, 1.2 equiv) was added dropwise to a suspension ofsodium hydride (2.2 g, 1.1 equiv, 60% dispersion in mineral oil) indimethylformarnmide (80 ml) under argon at 0° C. The reaction mixturewas stirred for 20 min prior to adding dropwise to a solution of2,4-dichloro-6,7-dihydro-5H-[1]pyrindine (Int. B5) (9.42 g, 1 equiv) indimethylformamide (70 ml) at 0° C., stirring was continued at ambienttemperature overnight. The solvent was evaporated and the residuepartitioned between water and ethyl acetate, the organic phase was driedand evaporated. Chromatography (silica, 10:1 toluene/ethyl acetate) gavethe title compound as an off white solid (8.99 g). ¹H-NMR (CDCl₃) δ 2.11(2H, m), 2.84 (2H, t), 2.97 (2H, t), 4.58 (2H, m), 5.30-5.46 (2H, m),5.94-6.07 (1H, m), 6.59 (1H, s); MS (APCI+) found (M+1)=210; C₁₁H₁₂³⁵CINO requires 209.

Intermediate B7—4-Allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine-1-oxide

A mixture of 3-chloroperbenzoic acid (19.5 g, 1.5 equiv) and4-allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine (Int. B6) (8.99 g, 1equiv) in dichloromethane (100 ml) was stirred at ambient temperatureunder argon for 4 h, washed with aqueous sodium bicarbonate, dried andevaporated. Chromatography (silica, 5% methanol in dichloromethane) gavethe title compound as a white solid (6.98 g). ¹H-NMR (CDCl₃) δ 2.19 (2H,qn), 2.97 (2H, t), 3.22 (2H, t), 4.57 (2H, m), 5.30-5.45 (2H, m),5.93-6.08 (1H, m), 6.80 (1H, s); MS (APCI+) found (M+1)=226; C₁₁H₁₂³⁵ClNO₂ requires 225.

IntermediateB8—4-Allyloxy-2-(4-fluorobenzylthio)6,7-dihydro-5H-[1]pyrindine 1-oxide

4-Fluorobenzyl mercaptan (1.59 g, 1.2 equiv) was added dropwise to asuspension of sodium hydride (0.372 g, 1.0 equiv, 60% dispersion inmineral oil) in dimethylformamide (30 ml) under argon at 0° C. Thereaction was stirred for 20 min, before adding dropwise to a solution of4-allyloxy-2chloro-6,7-dihydro-5H-[1]pyrindine-1-oxide (Int. B7) (2.1 g,1 equiv) in dimethylformamide (20 ml) at 0° C., stirring was continuedat ambient temperature overnight. The solvent was evaporated and theresidue partitioned between water and ethyl acetate, the organic phasewas dried and evaporated. Chromatography (silica, 3% methanol indichloromethane) gave the title compound as an off white solid (2.65 g).¹H-NMR (CDCl₃) δ 2.16 (2H, qn), 2.91 (2H, m), 3.18 (2H, t), 4.14 (2H,s), 4.43 (2H, m), 5.28 (2H, m), 5.84-5.97 (1H, m), 6.37 (1H, s), 7.00(2H, m), 7.39 (2H, m); MS (APCI+) found (M+1)=332; C₁₈H₁₈FNO₂S requires331.

IntermediateB9—2-(4-Fluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1]pyrindin-4-ol

A mixture of4-allyloxy-2-(4-fluorobenzylthio)-6,7-dihydro-5H-[1]pyrindine 1-oxide(Int. B8) (2.65 g) triphenylphosphine rhodium (I) chloride (0.740 g, 10mol %) and 1,4-diazobicyclo[2,2,2]octane (0.27 g, 30 mol %) in ethanol(90 ml) and water (10 ml) was heated to reflux overnight. The solventwas removed and the residue chromatographed (silica, 4% methanol indichloromethane) to yield the title compound as a brown solid (1.75 g).¹H-NMR (d₆-DMSO) δ 2.07 (2H, m), 2.80 (2H, t), 2.91 (2H, t), 4.14 (2H,s), 6.58 (1H, s), 7.15 (2H, m), 7.47 (2H, m); MS (APCI+) found(M+1)=292; C₁₅H₁₄FNO₂S requires 291.

Intermediate B10—4-Chloro-2-(2-(2,3 difluorophenyl)ethyl)quinoline

Butyllithium (4.76 ml, 2.5M in hexanes, 1 equiv) was added dropwise to asolution of 4-chloroquinaldine (2.4 ml, 1 equiv) in tetrahydrofuran (30ml) at −78° C. and the reaction mixture stirred for 15 min.2,3-Difluorobenzyl bromide (1.82 ml, 1.2 equiv) was added dropwise andstirring was continued for 1 h. After warming to room temperature thesolution was diluted with water and ethyl acetate and the organic phasedried and evaporated. Chromatography (silica, 10:1 petrol/ethyl acetate)gave the title compound as a white solid (3.16 g). ¹H-NMR (CDCl₃) δ 3.23(4H, m), 6.89-6.99 (3H, m), 7.33 (1H, s), 7.59 (1H, m), 7.74 (1H, m),8.04 (1H, d), 8.15 (1H, d); MS (APCI+) found (M+1)=304; C₁₇H₁₂ ³⁵CIF₂Nrequires 303.

The following intermediates were prepared by the method of intermediateB10 No. Precursor Structure Name B11 4-Fluorobenzyl bromide

4-Chloro-2-(2-(4-fluorophenyl)ethyl)- quinoline B12 3,4-Difluorobenzylbromide

4-Chloro-2-(2-(3,4-difluorophenyl)- ethyl)quinoline B132,4-Difluorobenzyl bromide

4-Chloro-2-(2-(2,4-difluorophenyl)- ethyl)quinoline B14 2-Fluorobenzylbromide

4-Chloro-2-(2-(2-fluorophenyl)- ethyl)quinoline B15 3-Chlorobenzylbromide

4-Chloro-2-(2-(3-chlorophenyl)- ethyl)quinoline B16 2,3,4-Trifluoro-benzyl bromide

4-Chloro-2-(2-(2,3,4-trifluoro- phenyl)ethyl)quinoline B173-Fluorobenzyl bromide

4-Chloro-2-(2-(3-fluorophenyl)- ethyl)quinoline

Intermediate B20—2,4-Dichloroquinoline

A mixture of 2,4-dihydroxyquinoline (14 g) and phosphorus oxychloride(40 ml) was heated to reflux overnight. The excess phosphorousoxychloride was evaporated off and the residue poured over ice. Theresulting solid was filtered off and dried to give the title compound asa brown solid (13.86 g). ¹H-NMR (CDCl₃) δ 7.82 (1H, m), 7.96 (2H, m),8.03 (1H, d), 8.21 (1H, dd); MS (APCI+) found (M+1)=198; C₉H₅ ³⁵Cl₂Nrequires 197.

Intermediate B21—4-Allyloxy-2-chloroquinoline

Allyl alcohol (7.1 ml, 1.2 equiv) was added dropwise to a suspension ofsodium hydride (3.83 g, 1.1 equiv, 60% dispersion in mineral oil) indimethylformamide (120 ml) under argon at 0° C. The reaction mixture wasstirred for 20 min prior to adding dropwise to a solution of2,4-dichloroquinoline (Int. B20) (17.26 g, 1 equiv) in dimethylformamide(80 ml) at 0° C., stirring was continued at ambient temperatureovernight. The solvent was evaporated and the residue partitionedbetween water and ethyl acetate, the organic phase was dried andevaporated. Chromatography (silica, toluene) gave the title compound asan off white solid (13.56 g). ¹H-NMR (CDCl₃) δ 4.77 (2H, m), 5.30-5.57(2H, m), 6.08-6.20 (1H, m), 6.73 (1H, s), 7.52 (1H, m), 7.71 (1H, m),7.92 (1H, d), 8.17 (1H, dd); MS (APCI+) found (M+1)=220; C₁₂H₁₀ ³⁵CINOrequires 219.

Intermediate B22—4-Allyloxy-2-(2,3-difluorobenzylthio)quinoline

2,3-Difluorobenzyl mercaptan (Int. B2) (2 g, 1.1 equiv) was addeddropwise to a suspension of sodium hydride (0.477 g, 1.05 equiv, 60%dispersion in mineral oil) in dimethylformamide (50 ml) under argon at0° C. The reaction mixture was stirred for 20min, before adding dropwiseto a solution of 4-allyloxy-2-chloroquinoline (Int. B21) (2.49 g, 1equiv) in dimethylformamide (30 ml) at 0° C. and stirring was continuedat ambient temperature overnight. The solvent was evaporated and theresidue partitioned between water and ethyl acetate, the organic phasewas dried and evaporated. Chromatography (silica, 2:1 petrol/toluene)gave the title compound as an off white solid (2.26 g). ¹H-NMR (CDCl₃) δ4.68 (4H, m), 5.34-5.53 (2H, m), 6.06-6.17 (1H, m), 6.54 (1H, s), 6.96(2H, m), 7.41 (2H, m), 7.65 (1H, dt), 7.90 (1H, dd), 8.11 (1H, dd); MS(APCI+) found (M+1)=344; C₁₉H₁₅F₂NOS requires 343.

The following intermediate was prepared by the method of intermediateB22: No. Precursors Structure Name B23 Int. B21, 4-Fluorobenzylmercaptan

4-Allyloxy-2-(4-fluorobenzylthio)quinoline

IntermediateB24—4-Allyloxy-2-(2,3-difluorobenzylthio)-6,7-dihydro-5H-[1]pyrindine-1-oxide

The title compound was prepared from Intermediate B7 and2,3-difluorobenzylthiol by the method of Intermediate B8.

IntermediateB25—2-(2,3-Difluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1]pyrindin-4-ol

The title compound was prepared from Intermediate B24 by the method ofIntermediate B9.

Intermediate B26—3-azaisatoic anhydride

To a stirring solution of 2,3-pyridinedicarboxylic anhydride (100 g, 1equiv) in anhydrous tetrahydrofuran (1 L) was added dropwise under argonat 38-46° C. over 1.25 h azidotrimethylsilane (97.9 ml, 1.1 equiv). Thetemperature was maintained at 45-50° C. for a further 2 h then themixture refluxed for 30 min, cooled to ambient temperature and ethanol(43 ml, 1.1 equiv) added dropwise. On stirring for 16 h an off-whitesolid was obtained which was filtered, washed and dried, to give thetitle compound (90.7 g). ¹H-NMR (d₆-DMSO) δ 7.25-7.35 (1H, m), 8.30-8.35(1H, dd), 8.65-8.7 (1H, dd), 11.3 (1H, br s)

Intermediate B30—6-Methyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione

Methyl 3-amino-5-methylthiophene-2-carboxylate (2.0 g, 11.7 mmol) andsodium hydroxide (0.89 g, 22.2 mmol) in 1:1 dioxan/water (40 ml) washeated at reflux for 18 h, then the solvent was removed in vacuo. Thecrude solid was dissolved in water (30 ml) and phosgene (15 ml, 20%solution in toluene, 30 mmol) was added over 10 min with stirring. Aftera further 30 min the precipitate was filtered off, washed with water anddried to yield the title compound (0.44 g). ¹H-NMR (CDCl₃) δ 2.5 (3H,s), 6.7 (1H, s), 12.5 (1H, s); MS (APCI+) found (M+H—CO₂)=140.

The following intermediates were prepared by the method of IntermediateB30: No. Structure Name B31

1H-thieno[3,2-d][1,3]oxazine-2,4-dione B32

1H-thieno[2,3-d][1,3]oxazine-2,4-dione B33

1H-thieno[3,4-d][1,3]oxazine-2,4-dione B34

2-methylthiazolo[4,5-d][1,3]oxazine-5,7-dione B35

2-methyl-2,7-dihydropyrazolo[3,4-d][1,3]oxazine-4,6-dione B36

2-(4-methoxybenzyl)-2,7-dihydropyrazolo[3,4-d][1,3]oxazine- 4,6-dioneB37

4-fluoroisatoic anhydride

The following intermediates were prepared by the method of Washbume andPark, Tet Lett. 243 (1976): No. Structure Name B40

5-ethyl-3H-[1,3]oxazine-2,6-dione B41

4,5-dimethyl-3H-[1,3]oxazine-2,6-dione

Intermediate B45—1,5,6,7-tetrahydrocyclopentald][1,3]oxazine-2-4-dione

Tetramethylsilylazide (1.28 ml, 1 equiv) was added dropwise to asolution of 1-cyclopentene-1,2-dicarboxylic anhydride (1.33 g, 1 equiv)in dichloromethane (20 ml) and the mixture was warmed to 35° C. Afterca. 4 h gas evolution had ceased. Ethanol (1 equiv) was added andstirring continued for 10 min, then the solvent was removed in vacuo andthe residue triturated with ether to obtain the title compound (0.74 g).¹H-NMR (d₆-DMSO) δ 2.00 (2H, m), 2.47 (2H, m), 2.68 (2H, m), 11.8 (1H,br s); MS (APCI−) found (M−1)=152; C₇H₇NO₃ requires 153.

The following intermediate was prepared by the method of Int. B45 No.Structure Name B46

5,6,7,8-tetrahydro- 1H-benzo[d][1,3]oxazine-2-4-dione

Intermediate B50—Ethyl(2,4-dioxo-4H-pyrido[2,3-d][1,3]oxazin-1-yl)acetate

A 2:1 mixture of 3- and 6-azaisatoic anhydride (3.55 g, 21.6 mmol)(Synthesis 1982, 11, 972) was added portionwise to a suspension ofsodium hydride (0.95 g, 60% in oil, 23.8 mmol) in DMF (40 ml). Afterstirring for 1 h, ethyl bromoacetate (2.64 ml, 23.8 mmol) was added. Thereaction mixture was stirred overnight. The solvent was removed underreduced pressure. Ice/water was added to the residue and stirred for 1h. The resulting pink solid was collected by filtration, washed withwater and dried under vacuum at 40° C. The product was a 4:1 mixture ofthe [2,3-d] and the [3,2-d]isomers. ¹H-NMR data of the title compound.¹H-NMR (d₆-DMSO) δ 1.21 (3H, t), 4.18 (2H, q), 4.92 (2H, s), 7.45 (1H,dd), 8.47 (1H, dd), 8.77 (1H, dd); MS (APCI+) found (M+1)=251;C₁₁H₁₀N₂O₅ requires 250.

The title compound could also be prepared by the following method:

To a stirring mixture of 3-azaisatoic anhydride (Int. B26) (84.36 g, 1equiv) and N,N-diisopropylethylamine (94 ml, 1.05 equiv) inN-methylpyrrolidone (420 ml) was added dropwise under argon at 45-50°C., ethyl bromoacetate (57 ml, 1 equiv). After 16 h at 50° C. themixture was cooled (ice bath) and water (560 ml) added with vigorousstirring. The solid which precipitated was filtered, washed with waterand partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. An insoluble solid was filtered off and discarded and theethyl acetate layer washed again with saturated sodium bicarbonate,dried (Na₂SO₄) and evaporated. The residue was triturated with a 1:1mixture of ether/light petrol, filtered, washed and dried to give thetitle compound as an off-white solid, yield (56.0 g).

The following intermediates were prepared by the method of IntermediateB50: No. Precursor Structure Name B51 Int. B40

ethyl (5-ethyl-2,6-dioxo-6H-[1,3]oxazin-3- yl) acetate B52 Int. B41

ethyl (4,5-dimethyl-2,6-dioxo-6H- [1,3]oxazin-3-yl) acetate B53 Int. B37

ethyl 7-fluoro-2,4-dioxo-4H-benzo[d][1,3]- oxazin-1-yl) acetate B54 Int.B30

ethyl (6-methyl-2,4-dioxo-4H- thieno[3,2-d][1,3]oxazin-1-yl) acetate B55Int. B33

ethyl (2,4-di-4H- thieno[3,4-d][1,3]oxazin-1-yl)acetate B56 Int. B31

ethyl(2,4-dioxo-4H-thieno[3,2-d]- [1,3]oxazin-1-yl)acetate B57 Int. B32

ethyl(2,4-dioxo-4H-thieno[2,3-d]- [1,3]oxazin-1-yl)acetate B58 Int. B34

ethyl(6-methyl-2,4-dioxo-4H- thiazolo[4,5-d][1,3]oxazin-1-yl)acetate B59Int. B35

ethyl(2-methyl-4,6-dioxo-2,4-dihydro-pyrazolo[3,4-d][1,3]oxazin-7-yl)acetate B60 Int. B36

ethyl (2-(4-methoxybenzyl)-4,6-dioxo-2,4-dihydropyrazolo[3,4-d][1,3]oxazin-7-yl)- acetate B61 Int. B45

ethyl (2,4-dioxo-1,5,6,7-tetrahydro- cyclopenta[d][1,3]oxazin-3-yl)acetate B62 Int. B46

ethyl (2,4-dioxo-5,6,7,8-tetrahydro-1H- benzo[d][1,3]oxazin-3-yl)acetate

Intermediate B70—5-(2,3-difluorophenyl)-3-oxopentanoic acid tert-butylester

To an ice cooled stirring suspension of sodium hydride (1.96 g, 49.1mmol, 60% dispersion in oil) in dry tetrahydrofuran (100 ml) was addeddropwise under an argon atmosphere tert-butylacetoacetate (7.4 ml, 44.6mmol). After a further 15 min, n-butyllithium (18.7 ml, 46.8 mmol, 2.5Min hexanes) was added dropwise maintaining the reaction temperaturebelow 10° C. 2,3-Difluorobenzyl bromide (11.08 g, 53.5 mmol) was addeddropwise 20 min later, then the mixture allowed to warm to ambienttemperature. After a further 15 min the reaction mixture was poured ontoa mixture of water (150 ml) and glacial acetic acid (10 ml), extracted 3times with ethyl acetate and the combined extracts washed with saturatedsodium hydrogen carbonate then brine, dried (MgSO₄) and evaporated to ayellow oil. Chromatography (fine silica, ethyl acetate-light petrol)gave the title compound as a yellow oil, yield 9.05 g (71%). ¹H-NMR(CDCl₃) δ 1.45 (9H, s), 2.84-2.91 (2H, m), 2.95-3.00 (2H, m), 3.35 (2H,s), 6.92-7.04 (3H, m).

IntermediateB71—(3-tert-butoxycarbonylmethyl-2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-4H-[1,8]naphthyridin-1-yl)aceticacid ethyl ester

To a stirring suspension of sodium hydride (0.562 g, 14.06 mmol, 60%dispersion in oil) in dry DMF (50 ml) was added dropwise5-(2,3-difluorophenyl)-3-oxopentanoic acid tert-butyl ester (Int. B70)(3.63 g, 12.78 mmol). After 10 min,(2,4-dioxo-4H-pyrido[2,3-d][1,3]oxazin-1-yl)acetic acid ethyl ester(Int. B50) (3.21 g, 12.78 mmol) was added and the mixture stirred for 16h. The solvent was evaporated and the residue treated with saturated aq.ammonium chloride and extracted 3 times with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄) and concentrated.Chromatography (fine silica, ethyl acetate-light petrol) gave the titlecompound as a light brown solid, yield 1.88 g (31%). ¹H NMR (d6-DMSO) δ1.31 (3H, t), 1.63 (9H, s), 2.95-3.03 (2H, m), 3.08-3.13 (2H, m), 4.27(2H, q), 5.31 (2H, s), 7.01-7.11(3H, m), 7.35-7.38 (1H, m), 8.67-8.71(2H, m).

The title compound was also made by the following method:

To an ice-cooled solution of intermediate B50 (55.9 g, 1 equiv) andintermediate B70 (63.5 g, 1 equiv) in dichloromethane (700 ml) was addeddropwise under argon over 45 min 1,8-diazabicyclo[5.4.0]undec-7-ene (40ml, 1.2 equiv). After 1 h the ice bath was removed and after a further2.5 h the mixture was washed with saturated aqueous ammonium chloride,dried (Na₂SO₄) and evaporated. The crude product was chromatographed(fine silica, ethyl acetate-dichloromethane) then triturated with lightpetrol to give the title compound (80.27 g).

The following intermediates were prepared by the method of IntermediateB71: No. Precursor Structure Name B72 Int. B51

2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-5-ethyl-4-oxo-4H-pyridin-1-yl]acetic acid, ethyl ester B73 Int. B52

2-[2-(2,3-difluorophenyl)ethyl)-3-tert-butoxycarbonyl-5,6-dimethyl-4-oxo- 4H-pyridin-1-yl]acetic acid, ethylester B74 Int. B54

5-[2-(2,3-difluorophenyl)ethyl)-6-tert-butoxycarbonyl-2-methyl-7-oxo-7H- thieno[3,2-b]pyridin-4-yl]acetic acid,ethyl ester B75 Int. B55

2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-4-oxo-4H-thieno[3,4-b]pyridin-1-yl]acetic acid, ethyl ester B76 Int. B58

2-[5-(2,3-difluorophenyl)ethyl)-6-tert-butoxycarbonyl-2-methyl-7-oxo-7H- thiazolo[4,5-b]pyridin-4-yl]aceticacid, ethyl ester B77 Int. B59

2-[6-(2,3-difluorophenyl)ethyl)-5-tert-butoxycarbonyl-2-methyl-4-oxo-4H- pyrazolo[3,4-b]pyridin-7-yl]aceticacid, ethyl ester B78 Int. B61

2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-4-oxo-5,6-trimethylenepyridin-1-yl]acetic acid, ethyl ester B79 Int. B62

2-[2-(2,3-difluorophenyl)ethyl)-3-tert- butoxycarbonyl-4-oxo-5,6-tetramethylenepyridin-1-yl]acetic acid, ethyl ester

Intermediate B80—5-(2,3-difluorophenyl)-3-oxopentanoic acid ethyl ester

Prepared from ethyl acetoacetate by the method of Int. B70. ¹H-NMR(CDCl₃) δ 1.27 (3H, t), 2.86-3.02 (4H, m), 3.43 (2H, s), 4.18 (2H, q),6.92-7.07 (3H, m).

Intermediate B91—Ethyl2-[6-(2-(2,3-difluorophenyl)ethyl)-2-(4-methoxybenzyl)-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]acetate

To sodium hydride (0.315 g) in dry DMF (8 ml) at 0° C. under argon wasadded a solution of intermediate B70 (2.23 g) in dry DMF (8 ml)dropwise. After stirring at 0° C. for 30 min, a solution of intermediateB60 (2.82 g) in dry DMF was added and the mixture allowed to warm toroom temperature. After 4 h at room temperature, the mixture was pouredinto saturated ammonium chloride solution and extracted with ethylacetate. The combined extracts were dried over MgSO₄ and evaporatedunder reduced pressure to give an oil that was chromatographed on silicagel. This gave a yellow oil (2.3 g). A portion of this material (0.50 g)in TFA (5 ml) was stirred at room temperature for 4 h, then evaporatedto dryness. A portion of the residue was added to diphenyl ether (5 ml),heated to reflux for 40 min, then cooled and poured into hexane. Theprecipitate was filtered off and washed with hexane to obtain the titlecompound. ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 2.81 (2H, m), 3.01 (2H, m),3.81 (3H, s), 4.25 (2H, q), 4.93 (2H, s), 5.27 (2H,s), 5.96 (1H, s),6.88-7.10 (5H, m), 7.23 (2H, d), 7.88 (1H, s).

Intermediate B92—Ethyl2-[6-(2-(2,3-difluorophenyl)ethyl)-4oxo-2,4-dihydropyrazolo[3,4-b]-pyridin-7-yl]acetate

A mixture of Int. B91 (0.48 g) and TFA (50 ml) was heated at reflux for17 h, then the TFA was removed in vacuo. The residue was extracted withdichloromethane, and the combined extracts were chromatographed (silica,10% methanol in dichloromethane) to obtain the title compound as a darksolid (0.23 g, 64%). ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 2.85 (2H, m), 3.02(2H, m), 4.25 (2H, q), 4.97 (2H,s), 6.01 (1H, s), 6.95-7.09 (3H, m),8.24 (1H, s).

IntermediateB93—5-(2-(2,3-Difluorophenyl)ethyl)-3-(pyrazol-4-ylamino)pent-2-enoicacid ethyl ester

4-Nitropyrazole (3.55 g, 1 equiv) in ethanol (150 ml) was hydrogenatedover 10% palladium on charcoal, then the catalyst was filtered off, Int.B80 (8.0 g, 1 equiv) was added and the solvent was removed in vacuo.Concentrated hydrochloric acid (0.5 ml) was added, and the mixture washeated to 100° C. under argon for 2 h. Ethyl acetate was added and thesolution was washed with aq. sodium bicarbonate, dried and evaporated.Chromatography (silica, dichloromethane/ethyl acetate) yielded the titlecompound as a pale solid (5.7 g, 56%). ¹H-NMR (CDCl₃) δ 1.29 (3H, t),2.48 (2H, t), 2.80 (2H, t) 4.15 (2H, q), 4.74 (1H, s), 6.78 (1H, m),6.95 (2H, m), 7.46 (2H, s), 9.75 (1H, s), 11.1 (1H, br s).

IntermediateB94—5-(2-(2,3-Difluorophenyl)ethyl)-2,4-dihydropyrazolo[4,3-b]pyridin-7-one

Intermediate B93 (6.7 g) was added portionwise to refluxing Dowtherm(100 ml) and heating was continued for 1 h. After cooling, the mixturewas poured into hexane and the precipitate was filtered off, washed withhexane and dried; yield 4.5 g (78%). ¹H-NMR (d₆-DMSO) _67 2.89 (2H, m),3.06 (2H, m), 5.81 (1H, s), 7.07-7.36 (3H, m), 7.76 (1H, s), 11.7 (1H,br s), 13.6 (1H, br s).

IntermediateB95—7-Chloro-5-(2-(2,3-difluorophenyl)ethyl)-2,4-dihydropyrazolo[4,3-b]pyridine

A mixture of Intermediate B94 (4.5 g) and phosphorus oxychloride (90 ml)was heated at reflux for 2 h, then excess phosphorus oxychloride wasremoved in vacuo and the residue was poured into water and basified withsodium bicarbonate. The product was extracted into ethyl acetate and theextracts dried and evaporated to obtain the title compound (4.6 g, 96%).¹H-NMR (CDCl₃) δ 3.22 (4H, m), 6.89-7.06 (3H, m), 7.21 (1H, s), 8.34(1H, s), 11.0 (1H, br s).

Intermediates B96 andB97—5-(2-(2,3-difluorophenyl)ethyl)-1-methyl-2,4-dihydropyrazolo[4,3-b]-pyridin-7-oneand5-(2-(2,3-difluorophenyl)ethyl)-2-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one

A mixture of Intermediate B95 (4.3 g, 1 equiv), sodium hydroxide (1.5 g,2.5 equiv) and 90% aq. ethanol (15 ml) was heated to reflux and asolution of iodomethane (1.82 ml, 2 equiv) in diethyl ether (15 ml) wasadded dropwise (CARE). After 3 h at reflux a further 2 equivalents ofiodomethane was added, and heating was continued for 2 h. The solventwas removed in vacuo, the residue was dissolved in ethyl acetate, andthe solution washed with water, dried and evaporated to obtain a crudemixture of products in a ratio of ca. 3:2. These were separated bychromatography (silica, dichloromethane-ethyl acetate). Early fractionsgave the 1-methyl isomer (Int. B96, 2.1 g); ¹H-NMR (CDCl₃) δ 3.17 (4H,m), 4.36 (3H, s), 6.90-7.04 (3H, m), 7.12 (1H, s), 8.15 (1H, s). Laterfractions gave the 2-methyl isomer (Int. B97, 1.2 g); ¹H-NMR (CDCl₃) δ3.16 (4H, m), 4.29 (3H, s), 6.90-7.04 (3H, m), 7.15 (1H, s), 8.14 (1H,s). The identity of the two isomers was confirmed by NOE experiments.

IntermediateB98—5-(2-(2,3-Difluorophenyl)ethyl)-1-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one

A mixture of Int. B96 (2.1 g), 2M hydrochloric acid (10 ml) and dioxan(3 ml) was heated at reflux for 4 days, then extracted withdichloromethane/methanol. Drying and evaporation of the extracts gavethe title compound (1.7 g). ¹H-NMR (d₆-DMSO) δ 2.98-3.14 (4H, m), 4.22(3H, s), 6.22 (1H, s), 7.12-7.33 (3H, m), 7.89 (1H, s), 13 (1H, v br s);MS (APCI+) found (M+1)=290; C₁₅H₁₃F₃N₂O requires 2.89.

IntermediateB99—5-(2-(2,3-Difluorophenyl)ethyl)-2-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one

Hydrolysis of Int. B97 was carried out by the method of Int. B98. ¹H-NMR(d₆-DMSO) δ 2.82 (2H, m), 3.03 (2H, m), 4.02 (3H, s), 5.66 (1H, s), 7.10(2H, m), 7.25 (1H, m), 8.00 (1H,s), 11.5 (1H, v br s); MS (APCI+) found(M+1)=290; C₁₅H₁₃F₃N₂O requires 289.

IntermediateB100—Dimethyloxosulphonium-2-(ethoxycarbonylmethylamino)benzoylmethylide

To a solution of trimethylsulphoxonium iodide (99 g, 0.45 mol) in DMSO(1 L) at 5° C. was added sodium hydride (19.4 g, 0.485 mol, 60% in oil)over 0.5 h and the solution stirred for a further 0.5 h until thereaction subsided. Ethyl2-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-yl)acetate (110 g, 0.44 mol) wasthen added to the solution over 0.33 h and stirred for a further 3 hafter which time the reaction mixture was heated at 50° C. for 1.5 h.After cooling to ambient the solution was poured onto ice and theprecipitate filtered off and washed with water then pentane. The solidswere dried in vacuo at 40° C. to provide the product (124.4 g, 94%).¹H-NMR (d₆-DMSO) δ 1.2 (3H, t), 3.5 (6H, s), 3.98 (2H, d), 4.15 (2H, q),5.46 (1H, s), 6.44 (1H, d), 6.52 (1H, t), 7.17 (1H, t), 7.47 (1H, d),8.93 (1H, br t).

The following intermediates were prepared by the method of intermediateB100 No. Precursor Structure Name B101 Int. B53

Dimethyloxosulphonium-2-(ethoxycarbonyl-methylamino)-4-fluorobenzoylmethylide B102 Int. B56

Dimethyloxosulphonium-3-(ethoxycarbonyl-methylamino)thien-2-ylcarbonylmethylide B103 Int. B57

Dimethyloxosulphonium-2-(ethoxycarbonyl-methylamino)thien-3-ylcarbonylmethylide B104 Int. B59

Dimethyloxosulphonium-3-(ethoxycarbonyl- methylamino)-1-methylpyrazin-4-ylcarbonylmethylide B105 Int. B50

Dimethyloxosulphonium-2-(ethoxycarbonyl-methylamino)pyridin-3-ylcarbonylmethylide

IntermediateB110—5-(1-(2,3-Difluorobenzylthio)-1-phenylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione

To hexane washed sodium hydride (7.45 g, 60% in oil) under argon, wasadded N-methylpyrrolidone (NMP) (270 ml) and the mixture cooled in anice-salt bath. 2,2-Dimethyl-1,3-dioxane-4,6-dione (26.8 g) was addedportionwise over 20 min keeping the temperature between 5-10° C.Effervescence was noted during the addition. The mixture was stirred atroom temperature for 1 h and phenylisothiocyanate (25.2 g) added over 15min. The mixture was stirred at room temperature for 2.5 h and cooled to15° C. in a cold water bath. 2,3-Difluorobenzyl bromide (38.6 g) wasadded over 10 min and stirred at room temperature overnight. The solventwas removed under reduced pressure and the residue partitioned betweenethyl acetate (1.2 L) and water. The organic layer was washed withfurther water and then brine and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue triturated with 40-60° C.petrol and the solid collected by filtration. Crystallisation frommethyl t.butyl ether gave the title compound as a pale yellow solid(51.4 g). ¹H-NMR (d₆-DMSO) δ 1.64 (6H, s), 4.16 (2H, d), 7.1-7.25 (2H,m), 7.25-7.5 (6H, m), 12.12 (1H, br s); MS (APCI−) found (M−1)=404;C₂₀H₁₇F₂NO₄S requires 405.

Intermediate B111—Ethyl2-(1-(2,3-difluorobenzylthio)-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-methyl)phenylamino)acetate

To hexane washed sodium hydride (1.0 g, 60% in oil) under argon, wasadded NMP (30 ml). A solution of5-(1-(2,3-Difluorobenzylthio)-1-phenylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione(10.0 g) (intermediate B110) in NMP (20 ml) was added by syringe over 15min at room temperature and stirred for 30 min. Ethyl bromoacetate (4.5g) was added and the mixture heated at 60° C. for 6 h. The mixture waspartitioned between ethyl acetate and water and the aqueous layerextracted with further ethyl acetate. The combined organic layers werewashed with further water and brine, dried over MgSO₄, and the solventremoved under reduced pressure. The orange oil so obtained wastriturated with diethyl ether/40-60° C. petrol to give a solid that wascollected by filtration. This solid was recrystallised from methylt-butyl ether to give the title compound (7.37 g). ¹H-NMR (d₆-DMSO) δ1.24 (3H, t), 1.55 (6H, br s), 4.19 (2H, q), 4.37 (2H, d), 4.81 (2H, brs), 6.85-7.5 (8H, 2xm).

IntermediateB112—2-(2-(2,3-Difluorophenyl)ethyl)-6-methylpyrido[1,2-a]pyrimid-4-one

A mixture of 2-amino-6-methylpyridine (0.55 g, 1 equiv), Int. B80 (1.5g, 1.15 equiv) and polyphosphoric acid (3 ml) was heated to 110° C. for6 h, then ice/water was added and the solution adjusted to pH 7 with aq.sodium hydroxide. The precipitate was filtered off, washed with waterand dried to obtain the title compound (1.3 g). ¹H-NMR (d₆-DMSO) δ 2.89(2H, m), 3.04 (3H, s), 3.12 (2H, m), 6.11 (1H, s), 6.62 (1H, d),6.95-7.04 (3H, m), 7.35-7.44 (2H, m); MS (APCI+) found (M+1)=301;C₁₇H₁₄F₂N₂O requires 300.

IntermediateB113—2-(2-(2,3-Difluorophenyl)ethyl)-7-methyl-1H-[1,8]naphthyridin-4-one

A mixture of Int. B112 (1.0 g) and diphenyl ether (10 ml) was heated toreflux for 4 h, then cooled to 0° C. The resulting solid was filteredoff, washed thoroughly with hexane and dried to obtain the titlecompound (0.67 g). ¹H-NMR (d₆-DMSO) δ 2.58 (3H, s), 2.91 (2H, m), 3.09(2H, m), 5.90 (1H, s), 6.62 (1H, d), 7.10-7.30 (4H, m), 8.26 (1H, d); MS(APCI+) found (M+1)=301; C₁₇H₁₄F₂N₂O requires 300.

Intermediate C1—2-(2,3-Difluorobenzylthio)-1H-quinolin-4-one

A mixture of 4-allyloxy-2-(2,3-difluorobenzylthio)quinoline (Int. B22)(2.24 g), triphenylphosphine rhodium (I) chloride (0.302 g, 5 mol %) and1,4-diazobicyclo[2,2,2]octane (0.147 g, 20 mol in ethanol (30 ml) andwater (1.5 ml) was heated to reflux for 4 h. The solvent was removed andthe residue partitioned between water and dichloromethane, the organicphase dried and evaporated. Chromatography (silica, 4% methanol indichloromethane) yielded the title compound as an off white solid (1.25g). ¹H-NMR (d₆-DMSO) δ 4.55 (2H, s), 6.37 (1H, br s), 7.15 (1H, m), 7.31(3H, m), 7.65 (2H, m), 8.02 (1H, d), 11.75 (1H, br s); MS (APCI+) found(M+1)=304; C₁₆H₁₁F₂NOS requires 303.

The following intermediate was prepared by the method of intermediateC1: No. Precursor Structure Name C2 Int. B23

2-(4-Fluorobenzylthio)-1H-quinolin-4-one

Intermediate C3—2-(2-(2,3-Difluorophenyl)ethyl)-1H-quinolin-4-one

4-Chloro-2-(2,3-difluorophenylethyl)quinoline (Int B10) (2.83 g) washeated to reflux in aqueous hydrochloric acid (2M, 15 ml) and dioxane (6ml) for 72 h. The reaction mixture was extracted with dichloromethane(90 ml) and methanol (10 ml), and the organic phase dried and evaporatedto give the title compound as a white solid (2.61 g). ¹H-NMR (d₆-DMSO) δ3.15 (4H, s), 6.46 (1H, s), 7.15 (2H, m), 7.27 (1H, m), 7.51 (1H, m),7.82 (2H, m), 8.15 (1H, d); MS (APCI+) found (M+1)=286; C₁₇H₁₃F₂NOrequires 285.

The following intermediates were prepared by the method of intermediateC3: No. Precursor Structure Name C4 Int. B11

2-(2-(4-Fluorophenyl)ethyl)-1H-quinolin-4-one C5 Int. B12

2-(2-(3,4-Difluorophenyl)ethyl)-1H-quinolin-4-one C6 Int. B13

2-(2-(2,4-Difluorophenyl)ethyl)-1H-quinolin-4-one C7 Int. B14

2-(2-(2-Fluorophenyl)ethyl)-1H-quinolin-4-one C8 Int. B15

2-(2-(3-Chlorophenyl)ethyl)-1H-quinolin-4-one C9 Int. B16

2-(2-(2,3,4-Trifluorophenyl)ethyl)-1H-quinolin-4-one  C10 Int. B17

2-(2-(3-Fluorophenyl)ethyl)-1H-quinolin-4-one

IntermediateC11-2-(4Fluorobenzylthio)-1,5,6,7-tetrahydro-[1]pyrindin-4-one

A mixture of2-(4-fluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1]pyrindin-4-ol (Int. B9)(1.54 g) and palladium/carbon (0.3 g, 20 wt %) in acetic acid (80 ml)was heated to 50° C. in an atmosphere of H₂ at 50 psi overnight. Thecatalyst was filtered off and solvent evaporated to give the titlecompound as a brown foam (1.21 g). ¹H-NMR (CDCl₃) δ 2.03 (2H, m), 2.81(4H, m), 4.14 (2H, s), 6.46 (1H, s), 6.89 (2H, m), 7.21 (2H, m); MS(APCI+) found (M+1)=276; C₁₅H₁₄FNOS requires 275.

The following intermediate was prepared by the method of Int. C11 No.Precursor Structure Name C12 Int. B25

2-(2,3-Difluorobenzylthio)-1,5,6,7-tetrahydro- [1]pyrindin-4-one

IntermediateD1—[2-(2,3-Difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]acetic acid tertbutyl ester

Butyllithium (2.5 M in hexanes, 1.52 ml, 1.05 equiv) was added dropwiseto a solution of 2-(2,3-difluorobenzylthio)-1H-quinolin-4-one (Int. C1)(1.1 g, 1 equiv) in tetrahydrofuran (20 ml) at 0° C. under argon. Thereaction mixture was stirred for 10 min prior to the addition of t-butylbromoacetate (1.76 ml), 3 equiv) and stirring continued for 60 h at 45°C. The solution was diluted with dichloromethane (40 ml) and washed withaqueous ammonium chloride and aqueous sodium bicarbonate, dried andevaporated. Chromatography (silica, 5% [2M ammonia in methanol] indichloromethane) yielded the title compound as a yellow foam (0.193 g).¹H-NMR (CDCl₃) δ 1.44 (9H, s), 4.29 (2H, s), 5.30 (2H, br s), 6.45 (1H,s), 7.06-7.24 (4H, m), 7.39 (1H, t), 7.63 (1H, dt), 8.41 (1H, dd); MS(APCI+) found (M+1) 418; C₂₂H₂₁F₂NO₃S requires 4.17.

The following intermediates were prepared by the method of IntermediateD1: No. Precursor Structure Name D2 Int. C3

[2-(2-(2,3-Difluorophenyl)ethyl)-4-oxo-4 H-quinolin-1-yl]acetic acidtert butyl ester. D3 Int. C2

[2-(4-Fluorobenzylthio)-4-oxo-4H- quinolin-1-yl]acetic acid tert butylester. D4 Int. C4

[2-(2-(4-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tertbutyl ester. D5 Int. C5

[2-(2-(3,4-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acidtert butyl ester. D6 Int. C6

[2-(2-(2,4-Difluorophenyl)ethyl)4-oxo-4H- quinolin-1-yl]acetic acid tertbutyl ester. D7 Int. C7

[2-(2-(2-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tertbutyl ester. D8 Int. C8

[2-(2-(3-Chlorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tertbutyl ester. D9 Int. C9

[2-(2-(2,3,4-Trifluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]acetic acidtert butyl ester. D10 Int. C10

[2-(2-(3-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid tertbutyl ester. D11 Int. B99

t-Butyl [5-(2-(2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-2,7-dihydropyrazolo[4,3-b]- pyridin-4-yl]acetate D12 Int.B98

t-Butyl [5-(2-(2,3-difluorophenyl)ethyl)1-methyl-7-oxo-1,7-dihydropyrazolo[4,3-b]- pyridin-4-yl]acetate D13 Int.C12

t-Butyl [2-(2,3-difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]acetate D14 Int. C3

Methyl 2-(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl)acetate D15 Int. B113

Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-7-methyl-4-oxo-4H-[1,8]naphthyridin-1-yl]- acetate

IntermediateD20—[2-(4-Fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-[1]pyrindin-1-yl]aceticacid tert butyl ester

A mixture of 2-(4-fluorobenzylthio)-1,5,6,7-tetrahydro-[1]pyrindin-4-one(Int. C11) (1.21 g, 1 equiv), t-butyl iodoacetate (3.18 g, 3 equiv) anddiisopropylethylamine (3.05 ml, 4 equiv) in dichloromethane (40 ml) wasstirred at ambient temperature under argon for 48 h, then the solutionwas washed with aqueous ammonium chloride and aqueous sodiumbicarbonate, dried and evaporated. Chromatography (silica, 5% methanolin dichloromethane) yielded the title compound as a off white foam(0.982 g). ¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.09 (2H, m), 2.84 (4H, m),4.07 (2H, s), 4.56 (2H, s), 6.45 (1H, s), 6.99 (2H, m), 7.25 (2H, m); MS(APCI+) found (M+1)=390; C₂₁H₂₄FNO₃S requires 389.

Intermediate D25—Ethyl(2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl)acetate

(a) A mixture ofdimethyloxosulphonium-2-(ethoxycarbonylmethylamino)benzoylmethylide(0.30 g, 1.01 mmol) (intermediate B100), carbon disulphide (0.13 ml,2.05 mmol) and diisopropylethylamine (0.35 ml, 2.02 mmol) in DMF (4 ml)was shaken under argon for 18 h then 2,3-difluorobenzyl bromide (0.42 g,2.02 mmol) added and the reaction shaken for a further 7 h. The solutionwas concentrated and the residues separated between ethyl acetate andwater. The organics were isolated, dried (MgSO₄) and concentrated.Purification by chromatography over silica eluting using a gradient fromdichloromethane to dichloromethane/ether 3:1 yielded the title compound(0.14 g, 36%). ¹H-NMR (d₆-DMSO) δ 1.2 (3H, t, J=7 Hz), 4.18 (2H, q, J=7Hz), 4.5 (2H, s), 5.3 (2H, s), 6.3 (1H, s), 7.18 (1H, m), 7.3 (1H, m),7.4 (2H, m), 7.6 (1H, d, J=8.5 Hz), 7.7 (1H, t, J=7 Hz), 8.1 (1H, d, J=8Hz). MS (APCI+) found (M+1)=390; C₂₀H₁₇F₂NO₃S requires 389.

(b) Ethyl(1-(2,3-difluorobenzylthio)-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)methyl)-phenylamino)acetate(intermediate B111) (0.85 g) under argon was stirred withtrifluoroacetic acid (10 ml) at room temperature overnight. The mixturewas evaporated under reduced pressure, dissolved in dichloromethane,washed with sodium bicarbonate solution and dried over Na₂SO₄. Thesolvent was removed under reduced pressure and the residue trituratedwith diethyl ether to give the title compound (0.43 g). ¹H-NMR (CDCl₃) δ1.27 (3H, t), 4.26 (2H, q), 4.29 (2H, s), 5.1 (2H, br s), 6.45 (1H,s),6.95-7.25 (4H, m), 7.39 (1H, t), 7.64 (1H, dt), 8.42 (1H, dd). Massspectrum as above.

IntermediateD26—(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo4H-[1,8]naphthyridin-1-yl)aceticacid ethyl ester

(3-tert-Butoxycarbonylmethyl-2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-4H-[1,8]naphthyridin-1-yl)aceticacid ethyl ester (Int. B71) (1.35 g, 2.86 mmol) was added portionwise toboiling diphenyl ether (10 ml) with stirring. After 20 min, the darksolution was allowed to cool to ambient temperature. Petroleum ether(b.p. 60-80° C.) was added to the point of cloudiness to give theproduct as a crystalline solid (0.724 g). ¹H NMR (d₆-DMSO) δ 1.19 (3H,t), 3.02-3.09 (4H, m), 4.16 (2H, q), 5.31 (2H, s), 6.10 (1H, s),7.13-7.21 (2H, m), 7.26-7.33 (1H, m), 7.46-7.49 (1H, m), 8.49 (1H, m),8.76 (1H, m). MS (APCI+), found (M+1)=373, C₂₀H₁₈F₂N₂O₃ requires 372.

The following intermediates were prepared by the method of IntermediateD26: No. Precursor Structure Name D27 Int. B72

Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-5-ethyl-4-oxo-4H-pyridin-1-yl]acetate D28 Int. B73

Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-5,6-dimethyl-4-oxo-4H-pyridin-1-yl]- acetate D29 Int. B74

Ethyl 5-[2-(2-(2,3- difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thieno[3,2-b]pyridin-4-yl]acetate D30 Int. B75

Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-thieno[3,4-b]pyridin-1-yl)- acetate D31 Int. B76

Ethyl [5-(2-(2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thiazolo[4,5-b]- pyridin-4-yl]acetate D32 Int. B77

Ethyl [6-(2-(2,3-difluorophenyl)ethyl)-2-methyl-4-oxo-4H-pyrazolo[3,4-b]- pyridin-7-yl]acetate D33 Int. B78

Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-1-yl]- acetate D34 Int. B79

Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-5,6-tetramethylenepyridin-1-yl]- acetate

The following intermediates were prepared by the method of IntermediateD25, method A: No. Precursor Structure Name D40 Int. B101

Ethyl [2-(2,3-difluorobenzylthio)-7-fluoro-4-oxo-4H-quinolin-1-yl]acetate D41 Int. B102

Ethyl [5-(2,3-difluorobenzylthio)-7- oxo-7H-thieno[3,2-b]pyridin-4-yl]-acetate D42 Int. B103

Ethyl [5-(2,3-difluorobenzylthio)-7- oxo-7H-thieno[2,3-b]pyridin-4-yl]-acetate D43 Int. B104

Ethyl [6-(2,3-difluorobenzylthio)-2- methyl-4-oxo-2,4-dihydro-pyrazolo[3,4-b]pyridin-7-yl]acetate D44 Int. B105

Ethyl [2-(2,3-difluorobenzylthio)-4-oxo-4H-[1,8]naphthyridin-1-yl]acetate

Intermediate D50—Ethyl[6-(2-(2,3-difluorophenyl)ethyl)-2-ethyl)-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]acetate

A mixture of Intermediate B92 (0.120 g, 1 equiv), potassium carbonate(0.070 g, 1.5 equiv) and iodoethane (1 equiv) in dry DMF (1.5 ml) wasstirred at room temperature for 4 days. Ethyl acetate was added, thesolution was washed with aq. sodium bicarbonate, then dried andevaporated. Chromatography (silica, 0-10% methanol in dichloromethane)gave the title compound as a brown solid (0.1 g, 77%). ¹H-NMR (CDCl₃) δ1.28 (3H, t), 1.54 (3H, t), 2.82 (2H, m), 3.02 (2H, m), 4.21-4.28 (4H,2xq), 4.93 (2H,s), 5.96 (1H, s), 6.93-7.08 (3H, m), 8.01 (1H, s); MS(APCI+) found (M+1)=390; C₂₀H₂₁F₂N₃O₃ requires 389.

The following intermediate was prepared by the method of Intermediate50: No. Precursor Structure Name D51 Int. B92, 2-iodo- propane

Ethyl [6-(2-(2,3-difluorophenyl)ethyl)-2-isopropyl-4-oxo-2,4-dihydropyrazolo- [3,4-b]pyridin-7-yl]acetate D52Int. B92, 1-bromo-2- methoxy- ethane Ethyl[6-(2-(2,3-difluorophenyl)ethyl)- 2-(2-methoxyethyl)-4-oxo-2,4-dihydro-pyrazolo[3,4-b]pyridin-7-yl]acetate

IntermediateE1—[2-(2,3-Difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]acetic acid

(a) Trifluoroacetic acid (0.5 ml) was added to a solution of Int. DI(0.193 g) in dichloromethane (5 ml) under argon, and stirred overnightat room temperature. Evaporation of the solvent and trituration withether gave the title compound as a white solid (0.153 g).

(b) To a solution of Int. D25 (21.56 g, 0.055 mol) in dioxan (200 ml)was added sodium hydroxide (6.0 g, 0.15 mol) in water (200 ml) and thesolution stirred for 2.5 h then concentrated. The residues weredissolved in water and acidified to pH 2 with 2M hydrochloric acid andthe precipitate collected and washed sequentially with water, ether andthen hexane. The solids were dried in vacuo at 40° C. to provide thetitle compound (20.0 g, 100%). ¹H-NMR (d₆-DMSO) δ 4.5 (2H, s), 5.2 (2H,br s), 6.3 (1H, s), 7.18 (1H, m), 7.3 (1H, m), 7.4 (2H, m), 7.6 (1H, d,J=8.5 Hz), 7.7 (1H, t, J=8 Hz), 8.1 (1H, d, J=8 Hz). MS (APCI+) found(M+1)=362; C₁₈H₁₃F₂NO₃S requires 361.

The following intermediates were prepared by the method of IntermediateE1(a): No. Precursor Structure Name E2 Int. D2

[2-(2-(2,3-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid E3Int. D3

[2-(4-Fluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-acetic acid E4 Int. D20

[2-(4-Fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-[1]pyridin-1-yl]-acetic acid E5 Int. D4

[2-(2-(4-Fluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid E6Int. D5

[2-(2-(3,4-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid E7Int. D6

[2-(2-(2,4-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acid E8Int. D7

[2-(2-(2-Fluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid E9Int. D8

[2-(2-(3-Chlorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid E10Int. D9

[2-(2-(2,3,4-Trifluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic acidE11 Int. D10

[2-(2-(3-Fluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid E12Int. D13

[2-(2,3-difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]aceticacid E13 Int. D11

[5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-2,7-dihydropyrazolo[4,3-b]pyridin-4-yl]- acetic acid E14 Int. D12

[5-(2-(2,3-difluorophenyl)ethyl)-1- methyl-7-oxo-1,7-dihydropyrazolo[4,3-b]pyridin-4-yl]- acetic acid

The following intermediates were prepared by the method of IntermediateE1(b): No. Precursor Structure Name E2 Int. D14

(2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl)acetic acid E21Int. D26

(2-[2-(2,3-difluorophenyl)ethyl]-4- oxo-4H-[1,8]naphthyridin-1-yl)aceticacid E22 Int. D40

[2-(2,3-difluorobenzylthio)-7-fluoro-4- oxo-4H-quinolin-1-yl]acetic acidE23 Int. D27

[2-(2-(2,3-difluorophenyl)ethyl)-5- ethyl-4-oxo-4H-pyridin-1-yl]aceticacid E24 Int. D28

[2-(2-(2,3-difluorophenyl)ethyl)-5,6-dimethyl-4-oxo-4H-pyridin-1-yl]acetic acid E25 Int. D41

[5-(2,3-difluorobenzylthio)-7-oxo-7H- thieno[3,2-b]pyridin-4-yl]aceticacid E26 Int. D29

5-[2-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thieno[3,2-b]pyridin-4-yl]acetic acid E27 Int. D30

[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-thieno[3,4-b]pyridin-1-yl]-acetic acid E28 Int. D31

[5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5-b]-pyridin-4-yl]acetic acid E29 Int. D43

[6-(2,3-difluorobenzylthio)-2-methyl- 4-oxo-2,4-dihydropyrazolo[3,4-b]-pyridin-7-yl]acetic acid E30 Int. D32

[6-(2-(2,3-difluorophenyl)ethyl)-2- methyl-4-oxo-4H-pyrazolo[3,4-b]-pyridin-7-yl]acetic acid E31 Int. D50

[6-(2-(2,3-difluorophenyl)ethyl)-2- ethyl-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]- acetic acid E32 Int. D51

[6-(2-(2,3-difluorophenyl)ethyl)-2- isopropyl-4-oxo-2,4-dihydropyrazolo-[3,4-b]pyridin-7-yl]acetic acid E33 Int. D15

[2-(2-(2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H-[1,8]naphthyridin-1-yl]acetic acid E34 Int. D44

[2-(2,3-difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]acetic acidE35 Int. D42

[5-(2,3-difluorobenzylthio)-7-oxo-7H- thieno[2,3-b]pyridin-4-yl]aceticacid E36 Int. D33

[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-trimethylenepyridin-1-yl]-acetic acid E37 Int. D34

[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-tetramethylenepyridin-1-yl]-acetic acid E38 Int. D52

[6-(2-(2,3-difluorophenyl)ethyl)- 2-(2-methoxyethyl)-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin- 7-yl]acetic acid

Example 1N-(2-Diethylaminoethyl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

A mixture of 2-(2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl)aceticacid (Int. E1) (0.15 g, 1 equiv),N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine(Int. A2) (0.145 g, 1 equiv),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (0.154 g, 1.2 equiv) and diisopropylamine(0.174 ml, 2.4 equiv) in dichloromethane (10 ml) was stirred at roomtemperature overnight, then washed with aqueous ammonium chloride andaqueous sodium bicarbonate. The organic layer was dried and evaporated,and the product purified by column chromatography (silica, 4% [2Mammonia in methanol] in dichloromethane). Product fractions wereevaporated to an off-white foam (0.201 g). This free base (0.201 g) wasdissolved in methanol (10 ml), tartaric acid (0.044 g) was added, themixture stirred for 5 min then evaporated. Trituration with ether gavethe bitartrate salt as an off-white solid (0.209 g). ¹H-NMR (d₆-DMSO, ca2:1 rotamer mixture) δ 1.03 (6H, m), 2.59 (6H, m), 3.41-3.62 (2H, m),4.26 (2H, 2x s), 4.65-4.83 (2H, m), 5.12-5.56 (2H, m), 6.44 (1H, 2x s),6.93-7.12 (3H, m), 7.30-7.75 (11H, m), 8.41 (1H, 2x d); MS (APCI+) found(M+1)=694; C₃H₃₆F₅N₃O₂s requires 693.

Example 2N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenylethyl)-4oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide

A mixture of2-[2-(2-(2,3-difluorophenyl)ethyl)-4oxo-4H-quinolin-1-yl]-acetic acid(Int. E2) (0.26 g, 1 equiv),N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine(Int. A2) (0.265 g, 1 equiv), HATU (0.28 g, 1.2 equiv) anddiisopropylamine (0.32 ml, 2.4 equiv) in dichloromethane (15 ml) wasstirred at room temperature overnight, then washed with aqueous ammoniumchloride and aqueous sodium bicarbonate. The organic layer was dried andevaporated, and the product purified by column chromatography (silica,2% [2M ammonia in methanol] in dichloromethane). Product fractions wereevaporated to an off-white foam (0.201 g). Trituration with ether gavethe title compound as a white solid (0.476 g). ¹H-NMR (d₆-DMSO, ca 2:1rotamer mixture) δ 0.93 (6H, 2x t), 2.38-2.80 (4H, m), 2.90-3.05 (4H,m), 3.45 (2H, m), 4.30-4.95 (4H, m), 5.23-5.58 (2H, m), 6.06 (1H, 2x s),7.14-7.38 (7H, m), 7.50-7.95 (7H, m), 8.16 (1H, m); MS (APCI+) found(M+1)=676; C₃₉H₃₈F₅N₃O₂ requires 675.

Example 3N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4ylmethyl)acetamidebitartrate

Treatment ofN-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide(Ex 2) with d-tartaric acid as for Example 1 gave the title compound asthe bitartrate salt.

Example 4N-(2Diethylaminoethyl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

The free base was prepared from Int. E12 and Int. A2 by the method ofExample 1. The bitartrate was formed as in example 1. ¹H NMR (d₆-DMSO) δ0.93, 0.99 (6H, 2x t), 1.95 (2H, m), 2.57-2.88 (8H, m), 3.21-3.60 (4H,m), 4.21 (2H, s), 4.23, 4.29 (2H, 2x s), 4.64, 4.75 (2H, 2x s), 5.01,5.22 (2H, 2x, s), 6.15, 6.17 (1H, 2x s), 7.12-7.21 (2H, m), 7.34-7.45(3H, m), 7.67 (1H, d), 7.71 (1H, d), 7.85 (4H, m); MS (APCI) found(M+1)=684; C₃₇H₃₈F₅N₃O₂S requires 683.

Example 5N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide

The free base was prepared from Int. E1 and Int. A42 by the method ofExample 1, except using DMF as solvent in place of dichloromethane. 1.97g of this material was crystallised from n.butyl acetate (10 ml) to givethe title compound (1.35 g). ¹H-NMR (CD₃OD) δ 1.7-2.05 (4H, m), 2.05-2.3(2H, 2xt), 2.5-2.65 (2H, m), 2.95-3.1 (2H, m), 3.3 (3H, s), 3.45-3.55(2H, m), 3.9-4.05+4.4-4.5 (1H, 2xm), 4.37+4.48 (2H, 2xs), 4.71+4.87 (2H,2xbr s), 5.31+5.68 (2H, 2xs), 6.44+6.52 (1H, 2xs), 6.95-7.3 (3H, m),7.35-7.85 (11H, m), 8.2-8.35 (1H, m); MS (APCI+) found (M+1) 736;C₄₀H₃₈F₅N₃O₃S requires 735.

Example 6N-(1-Methylpiperdin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

The free base was prepared from Int. E1 and Int. A5 by the method ofExample 1, except using DMF as solvent in place of dichloromethane.Chromatography (acetone to acetone/MeOH 4:1) yielded the free base (˜7:3rotomer mixture); ¹H-NMR (CDCl₃) δ 1.7-1.8 (3.7H, m), 1.9-2.15 (2.3H,m), 2.26 (2.1H, s), 2.3 (0.9H, s), 2.9 (1.4H, d, J=11.5 Hz), 2.98 (0.6H,d, J=10 Hz), 3.7 (0.3 H, m), 4.2 (1.4H, s), 4.27 (0.6H, s), 4.62 (0.7H,m), 4.69 (0.6H, s), 4.73 (1.4H, s), 5.01 (1.4H, br s), 5.35 (0.6H, brs), 6.41 (0.7H, s), 6.49 (0.3H, s), 6.9-7.2 (4H, m), 7.29-7.75 (10H, m),8.38 (0.7H, d, J=8 Hz), 8.4 (0.3H, d, J=8 Hz); MS (APCI+) found(M+1)=692; C₃₈H₃₄F₅N₃O₂S requires 691

Conversion to bitartrate salt was carried out as in Example 1.

Example 7N-(1-Methylpiperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

To a stirring mixture of intermediate A5 (12.53 g, 1 equiv) anddiisopropylethylamine (18.82 ml, 3 equiv) in dry THF (125 ml) under anargon atmosphere was added in one portionO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (16.65 g, 1.5 equiv). A solution of Int. E21(12.4 g, 1 equiv), in dry N-methylpyrrolidone (25 ml) and dry THF (100ml) was then added dropwise over 1.5 h. After 72 h the solvents wereevaporated under reduced pressure and the residue treated with aqueoussodium bicarbonate and extracted 3 times with ethyl acetate. Thecombined extracts were washed with aqueous sodium bicarbonate, aqueousammonium chloride then aqueous sodium bicarbonate, dried (Na₂SO₄) andevaporated. The residue was chromatographed (fine silica, 2M ammonia inmethanol/dichloromethane) and the product obtained dissolved indichloromethane and washed twice with 0.5M aqueous sodium hydroxide thenbrine, dried (Na₂SO₄) and the solvent evaporated. Crystallisation thenrecrystallisation from acetonitrile gave the free base, 10.75 g. Thismaterial (10.69 g, 1 equiv) together with L-tartaric acid (2.39 g, 1equiv) was dissolved in methanol (50 ml) and evaporated to a thick syrupwhich was triturated with ether to give the bitartrate salt as anoff-white solid (12.4 g). ¹H NMR (d₆-DMSO), δ 1.58-1.66 and 1.80-2.05(4H, m), 2.40-2.65 (5H, m), 2.93-3.19 (6H, m), 4.15 (2H, s), 4.16-4.38(1H, m), 4.62, 4.88, 5.42, 5.68 (4H, 4x s), 6.00, 6.03 (1H, 2x s),7.10-7.97 (12H, m), 8.48 (1H, m), 8.82-8.90 (1H, m); MS (APCI+) found(M+1)=675; C₃₈H₃₅F₅N₄O₂ requires 674.

Example 8N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide

To a stirring mixture of Int. A42 (14.12 g, 1 equiv) anddiisopropylethylamine (18.82 ml, 3 equiv) in dry THF (125 ml) under anargon atmosphere was added in one portionO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (16.65 g, 1.5 equiv). A solution of Int. E21(12.4 g, 1 equiv), in dry N-methylpyrrolidone (25 ml) and dry THF (100ml) was then added dropwise over 1.5 h. After 16 h the solvents wereevaporated under reduced pressure and the residue treated with 1Mhydrochloric acid (200 ml) and extracted 3 times with ethyl acetate. Thecombined extracts were washed with 1M hydrochloric acid (200 ml), brine,2M sodium hydroxide x2, dried (Na₂SO₄) and evaporated. The residue waschromatographed (fine silica, 2M ammonia in methanol/dichloromethane)and the oil obtained dissolved in ether and allowed to crystallise thenrecrystallised from dichloromethane/ether, yield 11.98 g (free base).13.64 g of title compound formed in the same manner as above wasrecrystallised from hot n.butyl acetate (70 ml) to give crystallinetitle compound (11.5 g). ¹H NMR (CD₃OD), δ 1.6-2.35 (6H, m), 2.45-2.65(2H, 2xm), 2.9-3.12 (4H, m), 3.12-3.35 (5H), 3.4-3.55 (2H, 2xt),4.17+4.40 (1H, 2xm), 4.71+4.93 (2H, s), 5.3-6.0 (2H, br), 6.26+6.31 (1H,2xs), 7.0-7.35 (3H, m), 7.3-7.4 (1H, d), 7.45-7.6 (2H, m), 7.6-7.9 (6H,m), 8.61 (1H, br t), 8.87 (1H, m); MS (APCI+) found (M+1)=719,C₄₀H₃₉F₅N₄O₃ requires 718.

Example 9N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

The free base was prepared from Int. E34 and Int. A42 by the method ofExample 7. Chromatography (EtOAc/acetone/MeOH 9:1) yielded the freebase. ¹H-NMR (d₆-DMSO) (˜1:1 rotomer mixture): δ 1.55 (1H, br d, 11 Hz),1.75-1.9 (4H, m), 2.15 (0.5H, t, J=8 Hz), 2.3 (1H, br t, J=12 Hz), 2.4(1H, br t, J=11 Hz), 2.66 (2H, m), 3.06 (2H, br t, 12 Hz), 3.2 (1.5H,s), 3.25 (1.5H, s), 3.3 (0.5H, t, J=7 Hz), 3.45 (2H, m), 4.1 (0.5H, m),4.2 (2H, s), 4.25 (0.5H, m), 4.5 (1H, s), 4.59 (2H, br s), 4.8 (1H, s),5.45 (1H, br), 5.75 (1H, br), 6.35 (0.5H, s), 6.38 (0.5H, s), 7.16 (1H,m), 7.2-7.4 (4H, m), 7.6 (2H, d, J=8 Hz), 7.7 (5H, m), 8.5 (1H, m), 8.7(2H, br), 8.82 (1H, m); MS (APCI+) found (M+1)=737; C₃₉H₃₇F₅N₄O₃Srequires 7.36.

Example 10N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-ethylbiphenyl-4-ylmethyl)acetamidebitartrate

The free base was prepared from Int. E1 and lift A29 by the method ofExample 1, except using DMF as solvent in place of dichloromethane. Thebitartrate salt was formed as in example 1. ¹H NMR (d₆-DMSO) δ 1.07 (3H,t), 1.22 (3H, t), 1.70-1.91 (4H, m), 2.37 (2H, m), 2.66 (4H, m), 3.20(2H, m), 4.12 (2H, s), 4.44 (3H, in), 4.70 (2H, m), 5.34 (2H, m), 6.27,6.33 (1H, 2x s), 7.11-7.76 (14H, m), 8.14 (1H, m); MS (APCI) found(M+1)=666; C₄₀H₄₁F₂N₃O₂S requires 665.

Example 11N-(1-Ethylpiperidin-4-yl)-2-[5-(2-(2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thiazolo[4,5-b]pyridin-4-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

Prepared from intermediate E28 (0.15 g) and intermediate A40 (0.149 g)using HATU (0.188 g) and diisopropylamine (0.172 ml) followed bybitartrate salt formation as in example 1. ¹H-NMR (d₆-DMSO) δ 0.95-1.15(3H, m), 1.6-2.1 (4H, m), 2.84 (3H, 2xs), 2.3-3.25 (10H, m), 4.14 (2H,s), 4.05-4.4 (1H, 2xm), 4.62+4.83 (2H, 2xbr s), 5.37+5.62 (2H, 2xbr s),6.02+6.05 (1H 2x s), 7.05-7.4 (4H, m), 7.5-7.7 (2H, m), 7.7-8.0 (5H, m);MS (APCI+) found (M+1)=709; C₃₈H₃₇F₅N₄O₂S requires 708.

Example 12(±)N-(1-Ethylpyrrolidin-3-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

Prepared from intermediate E2 (0.295 g) and A23 (0.30 g) using HATU(0.395 g) and diisopropylamine (0.3 ml) followed by bitartrate saltformation as in example 1. Spectral details of the free base are quotedbelow. ¹H-NMR (CDCl₃) δ 1.0-1.2 (3H, m), 1.8-2.15 (1H, m), 2.15-3.15 (11H, m), 4.6-5.2 (5H, m), 6.14+6.24 (1H, 2xs), 6.8-7.8 (14H, m), 8.25-8.45(1H, m); MS (APCI+) found (M+1)=6.74; C₃₉H₃₆F₅N₃O₂ requires 673.

Example 13(±)N-(1-Ethylpyrroldin-3-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

Prepared from intermediate E1 (0.312 g) and A23 (0.30 g) using HATU(0.395g) and diisopropylamine (0.3 ml) followed by bitartrate saltformation as in example 1. Spectral details of the free base are quotedbelow. ¹H-NMR (CDCl₃) δ 0.95-1.35 (3H, m), 1.8-2.8 (6H, m), 2.8-3.1 (2H,m), 4.19+4.25 (2H, 2xs), 4.5-5.5 (5H, m), 6.36+6.43 (1H, 2xs), 6.85-7.2(4H, m), 7.2-7.85 (10H, m), 8.25-8.5 (1H, m).

Example 14N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

Example 5 was converted to the bitartrate by the method of example 1.

Example 15N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N′-trifluoromethylbiphenyl-4-ylmethyl)acetamidedihydrochloride

Example 5 (1.0 g) was dissolved in isopropanol (10 ml) and 1M HCl indiethyl ether (4 ml) added. A thick precipitate formed. The mixture wasevaporated under reduced pressure and the residue dissolved inisopropanol (10 ml) with heating. On cooling a thick precipitate formedthat was filtered and dried. 0.2 g of this material was recrystallisedfrom further isopropanol (10 ml) to give the title compound (0.132 g).¹H-NMR (CD₃OD) δ 1.9-2.6 (4H, m), 3.0-3.5 (4H, m), 3.36+3.41 (3H, 2xs),3.5-3.8 (4H, m), 7/0-7.5 (4H, m), 7.5-7.65 (3H, m), 7.65-7.85 (5H, m),7.9-8.2 (2H, m), 8.4-8.55 (1H, m).

Example 16N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidemono paratoluenesulphonate

To a solution of example 5 (1.0 g) in tetrahydrofuran (THF) (10 ml) wasadded a solution of paratoluenesulphonic acid monohydrate (1 equiv) inTHF (5 ml) and the mixture stirred at 0° C. After 18 h, further THF wasadded and the mixture filtered and dried to give a solid (0.87 g). 0.7 gof this material was dissolved in THF (9 ml) and left at 0° C. for 18 h.The solid formed was filtered and washed with further THF (2 ml) anddried to give the title compound as a crystalline salt (0.67 g). ¹H-NMR(CD₃OD) δ 1.9-2.4 (4H, m), 2.31 (3H, s), 3.0-3.45 (7H, m′s), 3.5-3.75(4H, m), 4.3-4.55 (3H, m), 4.6-5.0 (2H, m), 5.40+5.73 (2H, 2xs), 6.47(1H, s), 6.95-7.3 (5H, m), 7.3-7.85 (13H, m) 8.2-8.35 (1H, m).

Example 17N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

Example 8 (8 g, 1 equiv) together with L-tartaric acid (1.67 g, 1 equiv)was dissolved in methanol (50 ml) and evaporated to a thick syrup whichwas triturated with ether to give the bitartrate salt as an off-whitesolid (9.54 g). ¹H NMR (CD₃OD), δ 1.53-1.64 and 1.70-1.87 (4H, m),2.15-2.43 and 2.55-2.69 (4H, m), 2.93-3.50 (11H, m), 4.05-4.32 (1H, m),4.19 (2H, s), 4.61, 4.87, 5.42, 5.67 (4H, 4x s), 6.08, 6.11 (1H, 2x s),7.09-7.94 (12H, m), 8.49 (1H, m), 8.82-8.90 (1H, m); MS (APCI+) found(M+1)=719, C₄₀H₃₉F₅N₄O₃ requires 718.

Example 18N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidemonohydrochloride

Example 8 (0.5 g) in methylethylketone (4 ml) was mixed with 4M HCl indioxane (0.174 ml). After 18 h at 0° C., a small amount of solid wasfiltered off. The mother liquors were evaporated under reduced pressureand the residue crystallised from acetone (4 ml). The solid so formedwas recrystallised from acetone to give the title compound (0.336 g). ¹HNMR (CD₃OD), δ 1.85-2.5 (4H, m), 2.95-3.15 (4H, br), 3.15-3.5 (7H,ss+m), 3.8 (4H, m), 4.38+4.61 (1H, br m), 4.74+4.97 (2H, 2xs), 5.4-6.0(2H, br), 6.29 (1H, s), 7.0-7.25 (3H, m), 7.3-7.65 (2H, m), 7.65-7.9(7H, m), 8.6-8.7 (1H, m), 8.8-8.9 (1H, m).

Example 19N-(1-(2-Methoxyethyl)piperidin-4yl)-2-[2-(2-(2,3difluorophenyl)ethyl)-4-oxo4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidedihydrochloride

Example 8 (0.321 g) in ethanol (3 ml) was stirred overnight with 4M HClin dioxan (0.25 ml). The solid was collected by filtration, washed withethanol and dried to give the title compound (0.31 g). ¹H NMR (CD₃OD), δ1.8-2.55 (4H, m), 3.0-3.8 (15H, m), 4.15-5.1 (3H, m), 5.6-6.6 (2H, br),6.94+6.97 (1H, 2xs), 7.0-7.25 (3H, m), 7.3-7.95 (9H, m), 8.8-8.95 (1H,m), 9.15-9.25 (1H, m).

The following Examples were made by the general method of Example 1,using an appropriate solvent such as dimethylformamide ordichloromethane: Ex. No. Precursors Structure Name 20 Int. E3 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(4- fluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 21 Int. E4 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(4- fluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethyl-biphenyl-4-ylmethyl)acetamide bitartrate 22 Int. E12 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2,3- trimethylenepyridin-1-yl]-N-(4′-difluorobenzylthio)-4-oxo-5,6- trifluoromethyl-biphenyl-4-ylmethyl)acetamide bitartrate 23 Int. E5 Int. A2

N-(2-Diethylaminoethyl)2-[2-(2- fluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 24 Int. E6 Int. A2

N-(2-Diethylaminoethyl)2-[2-(2- (3,4-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 25 Int. E8 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2-fluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 26 Int. E9 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (3-chlorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 27 Int. E21 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl)]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 28 Int. E21 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl)]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide 29 Int. E2 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 30 Int. E2 Int. A22

N-(2-Pyrrolidin-1-ylethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 31 Int. E2 Int. A41

N-(1-Isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 32 Int. E2 Int. A20

N-(2-piperidin-1-ylethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 33 Int. E22 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)7-fluoro-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 34 Int. E26 Int. A2

N-(2-Diethylaminoethyl)-5-[2-(2- (2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thieno[3,2- b]pyridin-4-yl]-N-(4′-trifluoro-methylbiphenyl-4-ylmethyl)- acetamide bitartrate 35 Int. E24 Int. A2

N-(2-Diethylaminoetbyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-5,6-dimethyl-4-oxo-4H-pyridin-1-yl]- N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 36 Int. E23 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-5-ethyl-4-oxo-4H-pyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 37 Int. E2 Int. A42

N-(1-(2-methoxyethyl)piperidin-4- difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 38 Int. E2 Int. A5

N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 39 Int. E27 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-thieno[3,4-b]pyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4-ylmethyl)acetaniide bitartrate 40 Int. E1 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- quinolin-1-yl]-N-(4′-trifluoro-difluorobenzylthio)-4-oxo-4H- methylbiphenyl-4-ylmethyl)- acetainidebitartrate 41 Int. E1 Int. A22

N-(2-pyrrolidin-1-ylethyl)-2-[2- (2,3-difiuorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-methyl)- acetamidebitartrate 42 Int. E30 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-methyl-4-oxo-4H-pyrazolo[3,4- b]pyridin-7-yl]-N-(4′-trifluoro-methylbiphenyl-4-ylmethyl)- acetamide bitartrate 43 Int. E1 Int. A41

N-(1-isopropylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 44 Int. E2 Int. A25

N-(1-ethylpiperidin-4-ylmethyl)-2- [2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 45 Int. E1 Int. A24

N-(3-Diethylaminopropyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 46 Int. E2 Int. A32

N-(4-pyrrolidin-1-ylbutyl)-2-[2-(2- (2,3-difluorophenyl)ethyl-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 47 Int. E2 Int. A24

N-(3-Diethylaminopropyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 48 Int. E1 Int. A32

N-(4-pyrrolidin-1-ylbutyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-methylbiphenyl-4-ylmethyl)- quinolin-1-yl]-N-(4′-trifluoro- acetamidebitartrate 49 Int. E25 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[5-(2,3- difluorobenzylthio)-7-oxo-7H-thieno[3,2-b]pyridin-4-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 50 Int. E28 Int. A2

N-(2-Diethylaxninoethyl)-2-[5-(2- (2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thiazolo[4,5- b]pyridin-4-yl[-N-(4′-trifluoro-methylbiphenyl-4-ylmethyl)- acetamide bitartrate 51 Int. E1 Int. A27

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-ethylbiphenyl- 4-ylmethyl)acetamide bitartrate 52Int. E2 Int. A27

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′- ethylbiphenyl-4-ylmethyl)- acetamide bitartrate53 Int. E1 Int. A28

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′- isopropylbiphenyl-4-ylmethyl)- acetamidebitartrate 54 Int. E2 Int. A28

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl-4-oxo-4H-quinolin-1-yl]-N-(4′- isopropylbiphenyl-4-ylmethyl)- acetamidebitartrate 55 Int. E34 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′- trifiuoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 56 Int. E34 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 57 Int. E2 Int. A26

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 58 Int. E1 Int. A26

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′- methylbiphenyl-4-ylmethyl)- acetamide bitartrate59 Int. E2 Int. A43

N-(1- Ethoxycarbonylmethylpiperidin-4- difluorophenyl)ethyl)-4-oxo-4H-methylbiphenyl-4-ylmethyl)- acetamide bitartrate 60 Int. E21 Int. A41

N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-yl]-N- (4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 61 Int. E1 Int. A30

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-dimethylbiphenyl-4-ylmethyl)- quinolin-1-yl]-N-(3′,4′- acetamidebitartrate 62 Int. E21 Int. A48

N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 63 Int. E1 Int.A31

N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(3′,4′- difluorobiphenyl-4-ylmethyl)- acetamidebitartrate 64 Int. E35 Int. A2

N-(2-Diethylaminoethyl)-2-[6-(2,3- difluorobenzylthio)-4-oxo-4H-thieno[2,3-b]pyridin-7-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 65 Int. E34 Int. A5

N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 66 Int. E2 Int.A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3,4-trifluorophenylethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 67 Int. E29 Int. A2

N-(2-diethylaminoethyl)-2-[6-(2,3- difluorobenzylthio)-2-methyl-4-oxo-2,4-dihydro- pyrazolo[3,4-b]pyridin-7-yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 68 Int. E31Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-ethyl-4-oxo-2,4- dihydropyrazolo[3,4-b]pyridin-7-yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate 69Int. E32 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-isopropyl-4-oxo-2,4- dihydropyrazolo[3,4-b]pyridin-7-yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate 70Int. E2 Int. A29

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-ethyl- biphenyl-4-ylmethyl)acetamide bitartrate71 Int. E28 Int. A41

N-(1-isopropylpiperidin-4-yl)-2-[5- (2-(2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-7H-thiazolo[4,5- b]pyridin-4-yl]-N-(4′-trifluoro-methylbiphenyl-4-ylmethyl)- acetamide bitartrate 72 Int. E28 Int. A42

N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[5-(2-(2,3-difluorophenyl)ethyl)-2-methyl-7- oxo-7H-thiazolo[4,5-b]pyridin-4-yl]-N-(4′-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate 73Int. E36 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 74 Int. E36 Int. A5

N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-l-yl]-N-(4]- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 75 Int. E36 Int. A42

N-(1-(2-methoxyethyl)piperidin-4- difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 76 Int. E36 Int. A41

N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-1-yl]N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 77 Int. E13 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[5-(2- (2,3-difluorophenyl)ethyl)-2-methyl-7-oxo-2,7- dihydropyrazolo‘4,3-b]pyridin-4- 4-ylmethyl)acetamidebitartrate 78 Int. E14 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[5-(2- (2,3-difluorophenyl)ethyl)-1-methyl-7-oxo-1,7- yl]-N-4′-trifluoromethylbiphenyl-dihydropyrazolo[4,3-b]pyridin-4- 4-ylmethyl)acetamide bitartrate 79 Int.E36 Int. A2

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 80 Int. E33 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7-methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 81 Int. E33Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7-methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 82 Int. E33Int. A5

N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7-methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 83 Int. E33Int. A41

N-(1-isopropylpiperidin-4-yl)-2-[2- (2-(2,3-difluorophenyl)ethyl)-7-methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 84 Int. E33Int. A42

N-(1-(2-methoxyethyl)piperidin-4- difluorophenyl)ethyl)-7-methyl-4-oxo-4H-[1,8]naphthyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 85 Int. E12 Int. A5

N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 86 Int. E12 Int. A40

N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 87 Int. E12 Int. A41

N-(1-isopropylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl[-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 88 Int. E12 Int. A42

N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-5,6-trimethylenepyridin-1-yl]- N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 89 Int. E37 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-5,6-tetramethylenepyridin-1-yl]-N- (4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 90 Int. E1 Int. A45

N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′- chlorobiphenyl-4-ylmethyl)- acetamide bit

Example 99N-(2-Diethylaminoethyl)-2-[4-oxo-2-(2-(2,3,4-trifluorophenyl)ethyl)-4H-quinolin-1-yl]-N-(4′-trifluoromethyl-biphenyl-4-ylmethyl)acetamidebitartrate

A solution ofN,N-diethyl-N′-(4′-trifluoromethyl-biphenyl-4-ylmethyl)ethane-1,2-diamine(0.242 g, 0.69 mmol) (Int. A2),1-(3-dimethylaminopropyl)3-ethylcarbodiimide (0.265 g, 1.39 mmol),1-hydroxybenzotriazole hydrate (0.02 g),2-(4-oxo-2-[2-(2,3,4-trifluorophenyl)ethyl]-4H-quinolin-1-yl)-aceticacid (Int. E10) (0.25, 0.69 mmol) and N,N-diisopropylethylamine (0.15ml, 0.86 mmmol) in dichloromethane (5 ml) was stirred at ambienttemperature overnight then washed with aqueous sodium bicarbonate andevaporated. The residue was purified by chromatography (10 g silicacartridge, dichloromethane-50% acetone/dichloromethane) and trituratedwith hexane to give the title compound as a white solid (0.23 g, 47%).¹H-NMR (d6 DMSO, rotamer mixture) δ 0.89-0.98 (6H, m), 2.33-2.67 (6H,m), 2.84-3.00 (4H, m), 3.45-3.61 (2H, m), 4.67/4.92 (2H, 2x s),5.24/5.50 (2H, 2x s), 6.02/6.05 (1H, 2x s), 7.19-7.20 (4H, m), 7.51-7.88(9H, m), 8.16 (1H, t); MS (APCI+) found (M+1)=694; C₃₉H₃₇F₆N₃O₂ requires693.

d-Tartaric acid (0.028 g, 0.19 mmol) was added to a solution of the freebase (0.13 g, 0.19 mmol) in methanol (5 ml) with stirring. The resultingsolution was evaporated to yield the salt (0.158 g). ¹H-NMR (d6 DMSO,rotamer mixture) δ 1.00 (6H, br s), 2.51-2.97 (10H, m), 3.64 (2H, br s),4.23 (2H, br s), 4.67/4.93 (2H, 2x s), 5.28/5.50 (2H, 2x s), 6.05 (1H,br s) 7.23-7.83 (13H, m), 8.17 (1H, s); MS (APCI+) found (M+1)=694;C₃₉H₃₇F6N₃O₂ requires 693.

The following compounds were prepared by the method of Example 99 Ex.No. Precursors Structure Name 100 Int. E7 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (2,4-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 101 Int. E11 Int. A2

N-(2-Diethylaminoethyl)-2-[2-(2- (3-fluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate

Example 105N-(piperidin-4yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

To intermediate F1 (0.55 g) in dichloromethane (6 ml) was addedtrifluoroacetic acid (2.5 ml) at room temperature. The mixture wasstirred for 2 h, the solvent removed under reduced pressure and diethylether added The solid so formed was filtered and washed with diethylether to give a solid that was partitioned between dilute sodiumbicarbonate and dichloromethane. The aqueous layer was extracted withfurther dichloromethane and the combined organic layers dried overK₂CO₃, filtered and evaporated under reduced pressure to a solid (0.42g). This free base (0.42 g) was dissolved in methanol (10 ml), tartaricacid (0.044 g) was added, the mixture stirred for 5min then evaporatedunder reduced pressure. Trituration with ether gave the bitartrate saltas an off-white solid (0.46 g). ¹H-NMR (d6 DMSO, rotamer mixture) δ1.6-2.05 (4H, m), 2.7-3.05 (2H, m), 3.1-3.4 (2H, m), 3.88 (2H, s),4.1-5.8 (7H, br ms), 6.27+6.32 (1H, 2xs), 7.05+7.55 (6H, m), 7.55-7.95(8H, m), 8.14 (1H, dt); MS (APCI+) found (M+1)=678; C₃₇H₃₂F₅N₃O₂Srequires 677.

The following examples were prepared by the method of Example 105: Ex.No. Precursors Structure Name 106 Int. F2

N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamidebitartrate 107 Int. F3

N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-5,6-trimethylenepyridin-1-yl]-N-(4′- trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate 108 Example 62

N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-4′- methyl)acetamide bitartrate 109 Example 96

N-(piperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-4′- trifluoromethylbiphenyl-4-yl-methyl)acetamide trifluoroacetate 110 Int. F4

N-(2-ethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide111 Int. F5

N-(2-ethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoro- methylbiphenyl-4-ylmethyl)- acetamide

Example 115N-(1-(2-hydroxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamidebitartrate

A mixture of Example 59 (0.18 g, 1 equiv), lithium borohydride (0.12 ml,2M in THF, 1 equiv) and dry THF (2 ml) was heated at reflux under argonovernight, then a further 0.06 ml portion of lithium borohydridesolution was added and heating continued for 4 h. Evaporation, aqueousworkup and chromatography (silica, 0-10% methanol in dichloromethane)gave the title compound (0.06 g). The bitartrate was prepared as inexample 1. ¹H-NMR (DMSO, rotamer mixture) δ 1.5-2.1 (4H, m), 2.5-3.65(12H, m), 4.15 (2H, s), 3.85-5.8 (5H, br m), 6.01+6.06 (1H, 2xs),7.0-7.95 (14H, m), 8.05-8.2 (1H, m); MS (APCI+) found (M+1)=704;C₄₀H₃₈F₅N₃O₃ requires 703.

Biological Data

1. Screen for Lp-PLA₂ Inhibition.

Enzyme activity was determined by measuring the rate of turnover of theartificial substrate (A) at 37 C in 50 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer containing150 mM NaCl, pH 7.4.

Assays were performed in 96 well titre plates.

Recombinant LpPLA2 was purified to homogeneity from baculovirus infectedSf9 cells, using a zinc chelating column, blue sepharose affinitychromatography and an anion exchange column. Following purification andultrafiltration, the enzyme was stored at 6 mg/ml at 4° C. Assay platesof compound or vehicle plus buffer were set up using automated roboticsto a volume of 170 μl. The reaction was initiated by the addition of 20μl of 10× substrate (A) to give a final substrate concentration of 20 μMand 10 μl of diluted enzyme to a final 0.2 nM LpPLA2.

The reaction was followed at 405 nm and 37° C. for 20 minutes using aplate reader with automatic mixing. The rate of reaction was measured asthe rate of change of absorbance.

Results

The compounds described in the Examples were tested as described aboveand had IC₅₀ values in the range <0.1 to 100 nM.

1. A compound of formula (I):

in which: R¹ is an aryl group, optionally substituted by 1, 2, 3 or 4substituents which may be the same or different selected fromC₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, hydroxy, halogen, CN, monoto perfluoro-C₍₁₋₄₎alkyl, mono to perfluoro-C₍₁₋₄₎alkoxyaryl, andarylC₍₁₋₄₎alkyl; R² is halogen, C₍₁₋₃₎alkyl, C₍₁₋₃₎alkoxy,hydroxyC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylthio, C₍₁₋₃₎alkylsulphinyl,aminoC₍₁₋₃₎alkyl, mono- or di-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylcarboxy,C₍₁₋₃₎alkylcarboxyC₍₁₋₃₎alkyl, and R³ is hydrogen, halogen, C₍₁₋₃₎alkyl,or hydroxyC₁₋₃₎alkyl; or R² and R³ together with the pyridone ringcarbon atoms to which they are attached form a fused 5-or 6-memberedcarbocyclic ring; or R² and R³ together with the pyridone ring carbonatoms to which they are attached form a fused benzo or heteroaryl ringoptionally substituted by 1, 2, 3 or 4 substituents which may be thesame or different selected from halogen, C₍₁₋₄₎alkyl, cyano,C₍₁₋₃₎alkoxyC₁₋₃₎alkyl, C₁₋₄₎alkoxy or C₍₁₋₄₎alkylthio, or mono toperfluoro-C₍₁₋₄₎alkyl; R⁴ is hydrogen, C₍₁₋₆₎alkyl which may beunsubstituted or substituted by 1, 2 or 3 substituents selected fromhydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹R¹⁰, NR⁷COR⁸,mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino andN-hydroxyC₍₁₋₆₎alkyl-N—C₍₁₋₆₎alkylamino; or R⁴ is Het-C₍₀₋₄₎alkyl inwhich Het is a 5- to 7- membered heterocyclyl ring comprising N andoptionally O or S, and in which N may be substituted by COR⁷, COOR⁷,CONR⁹R¹⁰, or C₍₁₋₆₎alkyl optionally substituted by 1, 2 or 3substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷,CONR⁹R¹⁰ or NR⁹R¹⁰, for instance, piperidin-4-yl, pyrrolidin-3-yl; R⁵ isan aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4substituents which may be the same or different selected fromC₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, arylC₍₁₋₆₎alkoxy, hydroxy,halogen, CN, COR⁷, carboxy, COOR⁷, NR⁷COR⁸, CONR⁹R¹⁰, SO₂NR⁹R¹⁰,NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alkyl and mono toperfluoro-C₍₁₋₄₎alkoxy; R⁶ is an aryl or a heteroaryl ring which isfurther optionally substituted by 1, 2, 3 or 4 substituents which may bethe same or different selected from C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy,C₍₁₋₆₎alkylthio, C₍₁₋₆₎alkylsulfonyl, arylC₍₁₋₆₎alkoxy, hydroxy,halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, SO₂NR⁹R¹⁰,NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C₍₁₋₄₎alkyl and mono toperfluoro-C₍₁₋₄₎alkoxy, or C₍₅₋₁₀₎alkyl; R⁷ and R⁸ are independentlyhydrogen or C₍₁₋₁₂₎alkyl, for instance C₍₁₋₄₎alkyl (e.g. methyl orethyl); R⁹ and R¹⁰ which may be the same or different is each selectedfrom hydrogen, or C₍₁₋₁₂₎alkyl, or R⁹ and R¹⁰ together with the nitrogento which they are attached form a 5- to 7 membered ring optionallycontaining one or more further heteroatoms selected from oxygen,nitrogen and sulphur, and optionally substituted by one or twosubstituents selected from hydroxy, oxo, C₍₁₋₄₎alkyl,C₍₁₋₄₎alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl, forinstance morpholine or piperazine; and X is a C₍₂₋₄₎alkylene group(optionally substituted by 1, 2 or 3 substituents selected from methyland ethyl), CH═CH, (CH₂)_(n)S or (CH₂)_(n)O where n is 1, 2 or
 3. 2. Acompound of formula (I) as claimed in claim 1 in which R¹ is phenyloptionally substituted by halogen, C₍₁₋₆₎alkyl, trifluoromethyl,C₍₁₋₆₎alkoxy.
 3. A compound of formula (I) as claimed in claim 1 inwhich R² and R³ together with the pyridone ring carbon atoms to whichthey are attached form a fused thiazolyl ring substituted by methyl, ora fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo,pyrido, thieno or pyrazolo ring.
 4. A compound of formula (I) as claimedin claim 1 in which R⁴ is selected from the group consisting of2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or1-ethylpyrrolidin-3-yl.
 5. A compound of formula (I) as claimed in claim1 in which R⁵ is phenyl.
 6. A compound of formula (I) as claimed inclaim 1 in which R⁶ is phenyl substituted by trifluoromethyl or ethyl inthe 4-position.
 7. A compound of formula (I) as claimed in claim 1 inwhich R⁵ and R⁶ together form a 4-(phenyl)phenyl or a2-(phenyl)pyridinyl substituent in which the remote phenyl ring may beoptionally substituted by halogen or trifluoromethyl, preferably at the4-position.
 8. A compound of formula (I) as claimed in claim 1 in whichX is C₍₂₋₄₎alkylene or CH₂S
 9. A compound of formula (I) as claimed inclaim 1 in which R¹ is phenyl substituted by 2,3-difluoro; R² and R³,together with the pyridone ring carbon atoms to which they are attached,form a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fusedbenzo or pyrido ring; R⁴ is 2-(diethylamino)ethyl,1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl,1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl; R⁵ is phenyl; R⁶ isphenyl substituted by ethyl or trifluoromethyl in the 4-position; and Xis CH₂S.
 10. A compound of formula (I) as claimed in claim 1 in which R¹is phenyl substituted by 2,3-difluoro; R² and R³, together with thepyridone ring carbon atoms to which they are attached, form a fusedthiazolyl ring substituted by methyl, or a benzo or pyrido ring; R⁴ is2-(diethylamino)ethyl, 1 -ethyl-piperidin-4-yl,1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or1-ethylpyrrolidin-3-yl; R⁵ is phenyl; R⁶ is phenyl substituted bytrifluoromethyl in the 4-position; and X is (CH₂)₂.
 11. A compound offormula (I) as claimed in claim 1 in which R¹ is phenyl substituted by2,3-difluoro; R² and R³, together with the pyridone ring carbon atoms towhich they are attached, form a fused benzo or pyrido ring; R⁴ is1-(2-methoxyethyl)piperidin-4-yl; R⁵ and R⁶ together form a4-(phenyl)phenyl substituent in which the remote phenyl ring issubstituted by trifluoromethyl, preferably at the 4-position; and X isCH₂S or (CH₂)₂.
 12. A compound of formula (I) as claimed in claim 1 andas named in any one of Examples 1 to
 115. 13. A compound of formula (I)as defined in claim 1 selected from the group consisting ofN-(1-(2-methoxyethyl)piperidin-4-y)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;or a pharmaceutically acceptable salt thereof, in particular thebitartrate, hydrochloride, dihydrochloride or paratoluenesulfonate salt.14. A pharmaceutical composition comprising a compound of formula (I) asclaimed in claim 1 and a pharmaceutically acceptable carrier.
 15. Acompound of formula (I) as claimed in claim 1 for use in therapy. 16.The use of a compound of formula (I) as claimed in claim 1 for themanufacture of a medicament for treating atherosclerosis.
 17. A methodof treating a disease state associated with activity of the enzymeLp-PLA₂ which method involves treating a patient in need thereof with atherapeutically effective amount of a compound of formula (I) as claimedin claim
 1. 18. A process for preparing a compound of formula (I) asdefined in claim 1 which process comprises reacting an acid compound offormula (II):

in which X, R¹, R² and R³ are as hereinbefore defined, with an aminecompound of formula (III):R⁶—R⁵—CH₂NHR⁴   (III) in which R⁴, R⁵ and R⁶ are as hereinbeforedefined; under amide forming conditions.